been assumed that the constituent cells are endowed with a certain
store of vitality for themselves and their descendants, and that
as this becomes exhausted the process of involution begins. This
conception of an inherent limit of life is probable from the analogy
of the existing limit of height and size, though in certain plants
and trees growth in size and length of days do not show a natural
limitation. The process of ageing of the cells is thus regarded as just
as much part of their development or life cycle as are their earlier
and progressive stages. The exception is that the reproductive cell
when it meets with its complement--the ovum with the spermatozoon--and
as it were with new blood, starts a fresh lease of life, and so in Sir
Edward Sharpey-Schafer’s[80] words “we can only be immortal through our
descendants.” That there is a more or less definite cycle during which
the cells multiply and after which they cease to do so receives support
from the anatomical and physiological changes in old age; thus the
ovary undergoes fibrotic atrophy and ceases to be actively functional
after the menopause. The atrophy or hypoplasia of the organs is due
to diminution of the proliferation of the constituent cells. This is
well shown in the lymphatic glands and spleen which are so active in
youth and atrophied in advanced life. Salimbeni and Gery[81] point out
that the hypoplasia in the woman aged 93 whom they minutely examined
was most prominent in the lymphatic tissues and the bone marrow which
have to supply the cells most constantly needed. Even in the lowest
forms of life senescence and death would occur in the absence of the
rejuvenescence associated with reproduction. In the complex congeries
of cells making up the higher animals and man this rejuvenescence does
not accompany reproduction, and the vitality of the constituent cells
diminishes until eventually atrophy and death supervene.
Many of the vital phenomena of cells may, as Martin Fischer,[82]
Lumière,[83] and others point out, be interpreted in terms of the
behaviour of simple hydrophilic colloids. Bechhold[84] has shown that,
like a simple colloidal jelly, the cells of the human body, which are
colloidal masses, lose their affinity for water progressively with age
and become less elastic; the water content of the fetus being 94 per
cent, as compared with 70 per cent at birth and 58 per cent in adult
life, thus recalling the old idea of the dryness of elderly bodies.
According to Marinesco[85] dehydration of the colloids in the cells is
an inherent progressive change in evolution and leads to senescence and
death. It has also been thought that as the result of differentiation
and metabolism the cell protoplasm may become overladen with products
inimical to its vitality, which it cannot, as can the protozoa, utilize
for rejuvenation, and which hinder metabolism. The micellae, or
aggregations of albumin constituting the colloids of the cells, alter
in structure and become more stable until the colloid state disappears
and the cell accordingly dies (Lumière, Danysz). Such changes must
obviously be greatly influenced, as H. Campbell[86] and others have
insisted, by their environment; the individual cells are in some degree
of material continuity by “protoplasmic bridges” which probably serve
not only for nutritional purposes but also for the transmission of
physiological impulses. It also appears that the life cycle of the
cell is determined not so much by time as by the interaction of the
tissues and the plasma. By cultivating connective tissue in the plasma
of chickens of different ages Carrel[87] showed that its growth was
more abundant in the plasma of younger chickens than in that of older
ones. Working on these lines Loeb and Northrop[88] concluded that the
duration of life was determined either by a substance leading to old
age or by the destruction of a substance which normally prevents old
age and natural death. More recently Carrel and Ebeling[89] found that
in these cultures of connective tissue the rate of multiplication of
fibroblasts and the duration of life _in vitro_ varied in inverse ratio
to the age of the animal from which the plasma was taken, and that
this depended on the presence of an inhibitory body in the plasma of
older animals. These experiments recall the practice centuries old of
transfusion of young persons’ blood into the old which, however, led to
disastrous results on account of a technique now known to be dangerous.
Whether with modern methods success will be obtained remains to be
proved, but probably repeated transfusions would be required. But to
return to the subject: Carrel, Champy, and Grandcourt have shown that,
with frequent washings to remove waste products, tissue cells can be
cultivated indefinitely for years _in vitro_, and in themselves have
an unlimited capacity for multiplication; it therefore appears that
the ageing of cells in the living organism is determined by extrinsic
factors in the plasma rather than by any inherent limitation in the
cells. In the ordinary conditions of life senescence of the cells
might be regarded as the result of increasing differentiation and,
possibly from accumulation of material which cannot be utilized for
rejuvenation, of diminished metabolic activity. In the physiological
life of gland cells, for example, the salivary glands and pancreas,
granules are manufactured and discharged, but the hypothetical material
which collects in elderly cells, of which pigment may possibly be an
example or the visible sign, remains in these cells and hampers their
functional activity. As atrophy of the functional cells and increase
of connective tissue are regarded as characteristic of senescence,
and a high proportion of cells as characteristic of embryonic life,
Robertson and Ray[90] suggest that the potential longevity of any
individual is determined by the relative velocities of anabolism in the
cells on the one hand, and in the fibrous tissue on the other hand. A
low rate of cellular anabolism increases the growth of the cells and
delays the increase of fibrous tissue; this they were able to effect
by feeding white mice with tethelin. The relations of the functionally
active cells and the connective tissues have also been investigated
by Nathan[91] and his collaborators, who bring forward experimental
evidence in favour of the modified view that while dense connective
tissue inhibits cellular proliferation, young loose connective tissue
favours the multiplication of cells in proportion as it approaches the
structure of the embryonic mesenchyma. Drew’s[92] observations on the
culture of tissues and tumours show that the stroma acts like embryonic
tissue in favouring growth.
To sum up: the cells of the complex organism depend for their duration
of life not so much on an inborn store of vitality as on metabolic
changes in the colloids which in their turn are modified or controlled
by extrinsic factors of various kinds.
RELATION OF THE ENDOCRINE GLANDS TO SENESCENCE
As the metabolic activities of the cells of the body generally are
markedly influenced by the secretions of the ductless glands, the
relations between these endocrine glands and senescence demand some
discussion.
The process of reproduction leads to rejuvenescence in the protozoa,
and it might therefore be imagined that in the higher animals continued
activity of the sexual glands would similarly exert a rejuvenating
influence on the remaining cells of the body. But the process of
specialization has gone so far in the cells of the higher animals
that the highly differentiated cells, especially of the nervous
system, cannot fairly be compared with the constituent molecules of a
unicellular organism. As sexual activity is the biological reason for
existence and as in vigorous men sexual power may last long beyond the
usual period, man being regarded as old as his sexual glands, it has
been widely imagined that the functional activity of the sex glands is
in some way a cause, rather than a manifestation, of the preservation
of bodily vigour, and conversely that failure and atrophy of the sexual
glands cause old age and senility. There is an attraction, though
not without the danger of fallacies, in interpreting the words of
older writers as prophetic anticipations of quite modern knowledge.
But with this caution in mind there is some ground for crediting
Hufeland[93] with some idea of the internal secretion of the sexual
glands: as long ago as the end of the eighteenth century he wrote “the
organs of generation have the power of secreting the finest and most
spiritual parts of our nourishment; but at the same time they are so
organised that these perfected and ennobled juices can again return
and be received into the blood. Like the brain, therefore, they belong
to those important organs which serve for bringing to perfection and
ennobling our organic matter and power, and even ourselves.”
Since 1889 when Brown-Séquard, at the age of 72 (6 years before his
death) put forward the idea that rejuvenation could be brought about
by the hypodermic injection of testicular emulsion, the view that old
age and senile changes are due to failure of the glands of internal
secretion has become popular. The thyroid (V. Horsley, Léopold-Lévi),
the testis and ovary, or most or all of the glands (pluriglandular
insufficiency) have been incriminated; Lorand,[94] indeed, regards old
age as a disease caused by degeneration of not one but several of the
endocrine glands, Biedl[95] expresses much the same view in referring
old age to a disturbance of the endocrine balance, and Berman[96] in a
recent semi-popular book states that old age is an exhaustion permanent
and irreparable of all the glands of internal secretion; like Lorand he
ascribes considerable importance to failure of the internal secretions
of the sexual glands. It is highly desirable to arrive at some
conclusion as to the relation between changes in the glands of internal
secretion and senescence, for in medical practice this conception
of cause and effect has been acted upon; various glandular extracts
have been employed to counteract and delay the disabilities that may
accompany advancing years and, though not so freely, operations, viz.,
ligature of the vas deferens and implantation of testicular grafts,
have been carried out.
Lydston[97] implanted testes from boys recently dead into men
with atrophied or destroyed testes and reported improvement.
Stanley and Kelker[98] implanted 11 cases with testicular
grafts obtained from executed criminals, and 5 cases with the
testes of rams, obtaining improved general condition, though
not claiming that life was prolonged. Stanley[99] injected by
means of a large syringe strips of testes of rams, goats, or
bears under the skin of the abdomen of more than 300 prisoners,
and stated that conditions of neurasthenia and senility were
relieved.
The stimulating effect of thyroid secretion on growth and metabolism,
shown both experimentally and clinically in the therapeutic triumphs
of thyroid treatment in myxoedema and hypothyroidism, seems to justify
the view that failure of thyroid function plays an important part in
reducing the capacity for multiplication and regeneration of cells.
Between the manifestations of hypothyroidism and those of old age there
are undoubtedly striking resemblances, such as the dry skin, the loss
of hair, the diminished mental and bodily energy, and the increased
amount of interstitial fibrous tissue. In some respects myxoedema and
cretinism imitate the senile state; myxoedema has indeed been described
as more than a simulation and as the best example of secondary senilism
(Hastings Gilford[100]); but this is a very different condition from
healthy old age which does not present the picture of complete loss
of thyroid function; old age therefore cannot be regarded as due to
athyroidism. Usually atrophy of the thyroid accompanies and corresponds
to that of the senescent body as a whole. No doubt pathological changes
may occur in the thyroid, especially in women, during advancing years,
and it is in such instances that thyroid feeding produces so much
improvement that it has revived in our day the hope of an elixir of
life and perpetual youth. It is not improbable that the administration
of thyroid gland extract may, by preventing high blood pressure, delay
or obviate the onset of arteriosclerosis, and so stave off senility
due to this cause, but this is pathological old age and not the
physiological involution.
In addition to the seminal tubules and ova, which provide their
external secretion, the testes and ovaries contain the interstitial
cells described by Bouin and Ancel[101] or, in Steinach’s phrase, “the
puberty gland”; the germ cells and the interstitial cells differ from
each other in structure, function, and reaction to external influences;
thus the germ cells though dominant are more susceptible to damage,
for example by ligature of the vas deferens, _x_-rays, alcoholism,
or pressure, as in the case of a cryptorchid. It is stated that when
the seminal tubules are active and prominent the interstitial cells
are scanty, and conversely that when the seminal tubules atrophy the
interstitial cells multiply; Lipschülz, Ottow, Wagner, and Bormann[102]
showed that hypertrophy of the interstitial cells as observed in
various experimental conditions depends on local factors in the testes
and has nothing to do with their internal secretion in relation to the
body as a whole. After ligature of the vas deferens in animals there
are, according to Steinach, Kuntz,[103] and others, two stages (1) the
seminal tubules atrophy while the interstitial cells multiply, and
(2) after some time the seminal tubules regenerate while a certain
amount of increase in the interstitial cells persists. Nathan[104]
ascribes the regeneration of the seminal tubes to the influence of the
interstitial cells, which he considers act like young connective tissue
by favouring growth. The interstitial cells of Leydig in the testis and
the interstitial or lutein cells of the ovary are generally regarded
as responsible by their lipoid internal secretion or hormone for the
secondary sex characteristics (Bouin and Ancel, K. Sand[105]), though
Blair Bell[106] and Sternberg[107] deny this. Sir Frederick Mott,[108]
who has extensively investigated the interstitial cells, especially in
connexion with dementia praecox and other forms of mental degeneration,
concludes that in fetal life they act as sex determinants, and that
later in life they are responsible for the sexual appetite. It has
been argued that atrophy of the interstitial cells is the cause of
senescence. Against this view is Sir Frederick Mott’s observation
that after birth the interstitial cells undergo progressive atrophy
and disappear, that they reappear and are in a state of functional
activity at puberty (a sequence of events described by Aron[109] as two
different interstitial glands), and that they are present in extreme
old age; Retterer[110] also described their presence in the testes of
men over 70 years of age. So far it might be concluded that changes
in old age, such as diminution in number and pigmentation, shown by
the interstitial cells, are not the cause but an accompaniment of
senescence.
Kenneth Walker’s[111] observation that the interstitial cells of the
testis show a gradual diminution in number from the age of about
30 years, might be quoted in favour of the contention that atrophy
of these cells plays a part in the production of senescence. In
addition there are the dramatic experiments on rats carried out by
Eugen Steinach,[112] who was formerly Professor of Physiology in
the German University of Prague and since 1912 has been Director of
the Physiological Section of the Experimental Biological Institute
at Vienna. He found that in apathetic senile rats with degenerative
changes in the thyroid, pituitary, and interstitial cells ligature
or section of one vas deferens causes atrophy of the seminal tubes
and active growth of the interstitial cells; the hormone thus
provided stimulates the thyroid, pituitary, and brain, and the rat
is rejuvenated, the sexual instincts and emotions become active, and
the rat may have offspring; when relapse into senility occurs, a
repetition of the operation on the other side brings about a further
rejuvenation; and later the same result is effected by grafting the
testes of a young rat. In this way life is definitely prolonged. This
procedure has been advocated in man with some success by Steinach;
Lichtenstern of Vienna, who has done 36 such operations and 21
implantations on account of senile changes, has not encountered any bad
results, but admits that he has not been uniformly successful, and that
the number of cases is not sufficient to justify a final conclusion.
From observation in Vienna Benjamin[113] estimated that the operation
was followed by no results at all in from 10 to 20 per cent of the
cases. Obviously a considerable time must elapse before any decision as
to prolongation of life can thus be assured.
In the autumn of 1921 a man aged 70 was advertised to speak
at the Albert Hall on “How I was made 20 years younger by the
Method of Dr. Steinach of Vienna,” but he died on the morning
of the day from pneumonia (Benjamin[113]), the necropsy not
revealing, so it is said, any trace of an operation; the
hypertrophy of the interstitial cells, however, may have been
induced by the exposure of the testes to _x_-rays.
Steinach’s observations naturally aroused great interest and have
been repeated with discordant results by a number of investigators:
Simmonds[114] and Tiedje[115] have failed to confirm the occurrence
of the changes in the testes after vasectomy; and Romeis[116] and
Marinesco[117] have not obtained the striking clinical results
described by Steinach. Levy Lenz and Schmidt,[118] however, report
rejuvenation in 23 out of 24 cases of vasectomy, and Voronoff
encouraging results from implantation of chimpanzee’s testes into man.
But Marinesco compares Steinach’s published results with those of
Brown-Séquard.
It may be added that the operation of ligature of the vas deferens
which was performed some 25 years ago, before prostatectomy became
established, in order to cause atrophy of enlarged prostate, was not
noticed to be followed by rejuvenescence. Mr. C. Mansell-Moullin, who
published[119] a series of 14 such cases, has kindly informed me that
his patients did not show any evidence of such a change. Romeis has
also raised this objection to Steinach’s results which it has been
thought might be explained by suggestion (Freudenberg)--a view hardly
tenable in the light of the remarkable results described in animal
experiments.
The internal secretion of the ovary has never been isolated, and the
evidence of its existence rests on the results of removal. Castration
in men and in women does not bring on the phenomena of old age,
though this operation is followed by well-marked changes as regards
the secondary sex-characters, and, according to Voronoff, eunuchs
are short-lived. It may also be pointed out that the obesity so
common after castration is not a feature of “the lean and slippered
pantaloon.” Further, after the menopause the ovaries undergo fibrotic
atrophy, and it appears from Professor Turnbull’s observations (_vide_
p. 114) that the interstitial cells are very scanty or absent; further
observations are necessary as to the presence of interstitial cells in
senescent ovaries, but presuming that they are scanty it would follow,
on the hypothesis that the interstitial cells exert an influence
in preventing the onset of old age, that women should become old
much sooner than men in whom the interstitial cells are apparently
much more in evidence. It cannot of course be admitted that such a
difference in the sex incidence of old age exists. The improved health
and rejuvenation after _x_-ray treatment for metrorrhagia and uterine
fibromyomas at the climacteric or post-climacteric age have been
regarded by Steinach and Bordier as due to hypertrophy of the ovarian
interstitial cells following induced atrophy of the ova, but to accept
this there must be definite evidence that the interstitial cells are
increased in number. Harrower’s[120] dictum that the absence of a
hormone provided by the interstitial cells is responsible for premature
senility does not appear to be borne out by our present knowledge, but
a great deal of further work must be done before a final decision is
justified.
Testicular and ovarian extracts, often in combination with those of the
thyroid and pituitary, which are known to have a definite physiological
action, have been extensively used as a panacea. But is there any
undeniable evidence that the extracts of testis and ovary so far
employed have any effect apart from that of suggestion? According to
Frank[121] the available ovarian preparations are defatted and thus
deficient in the potent lipoid extracts; and very serious doubts as to
the activity of testicular extracts have been expressed by Professor
Cushny.
The possibility must be borne in mind that the use of thyroid and
other gland extracts that have a definite effect on metabolism is not
devoid of risk to cells that are gradually undergoing involution;
for, by stimulating metabolism unduly, the existing vitality may be
prematurely exhausted and, though for a time there is a gratifying show
of energy, it is but a flash in the pan that precedes a more rapid loss
of function. We are irresistibly reminded that “no man putteth new wine
into old bottles: else the new wine doth burst the bottles.”
At the present time it would be unwise to express a dogmatic opinion
about the relation of the endocrine glands to normal old age. That old
age is due to endocrine insufficiency or loss of balance cannot be
regarded as proved, and it is probably safer to regard changes, such
as atrophy, in the various glands of internal secretion as concomitant
with, rather than causal of, those in the senescent body.
METCHNIKOFF’S PATHOLOGICAL EXPLANATION
As an alternative to the belief that there is an inherent quantum
of vitality which may be harmfully or beneficially influenced by
environment and the wear and tear of life, it has been suggested that
the process of ageing depends solely on external factors and that
either there is no intrinsic limitation to the life of the organism or
that the possibility is entirely cast into the shade by predominance of
extrinsic influences. This doctrine is free from any tinge of fatalism
and has the advantage that it is a direct stimulus to efforts in the
direction of hygiene in all its forms; for as things are now old age
owes its discomforts to superadded and in most instances avoidable
complications. Élie Metchnikoff, as is well known, attributed the
senile accompaniments of advanced years to pathological and preventible
causes, namely toxaemia induced by alcohol, syphilis, and especially
by bacterial activity in the colon which in common with Barclay-Smith
and Arbuthnot Lane, he regarded as a harmful phylogenetic relic,
this point of view being expressed by the epigram “the longer the
colon the shorter is life.” He considered that the putrefactive
bacteria in the colon produce phenol, indol, skatol, and aromatic
bodies which cause degenerative changes in the cells of the body;
and that the more resistant macrophages, which do not attack healthy
tissues, absorb the damaged cells. He therefore employed means to
prevent excessive bacterial activity in the large intestine, and in
addition to care in diet so as to diminish the risk of introducing
bacteria into the alimentary canal, he advocated the destruction of
putrefactive bacteria in the colon by means of sour milk and cultures
of _Bacillus bulgaricus_, which form lactic acid and thus render the
contents of the bowel acid and unsuitable for the growth of the harmful
micro-organisms. Metchnikoff thoroughly practised his doctrine, but he
did not begin his regime until he was well over fifty, and, in spite of
several severe illnesses which had damaged his heart, he lived longer
than any of his family and passed the 70th milestone. His views on the
method of production of senility aroused great interest and criticism
not only from Marinesco,[122] Léri,[123] Sand, Laignel-Lavestine,
and Voisin, who disputed the reality of the macrophages devouring
the cells of the central nervous system, and Ribbert[124] who denied
the existence of such a physiological intoxication and ascribed old
age and death to the inevitable physico-chemical changes incident
to life, but also from Salimbeni and Gery,[125] working in the
Pasteur Institute, who while supporting most of his contentions did
not consider that they provided the whole explanation, _e.g._, the
involution of the ovaries at a fixed age was not thus accounted for.
The means Metchnikoff advised for the postponement of senility and
death were on much broader lines than the popular conception summed
up by “sour milk” might suggest, for he expounded the philosophy of
orthobiosis or a correct method of living.