V THE CAUSES OF SENESCENCE AND GENERAL ATROPHY: LIMITED VITALITY OF CELLS—INFLUENCE OF THE ENDOCRINE GLANDS—METCHNIKOFF’S PATHOLOGICAL EXPLANATION SENESCENCE AND CARCINOMA

The causation of old age is so complex that it is not possible to argue with any conviction that any one of the following explanations exclusively solves the problem satisfactorily.

Limited Vitality of the Cells

To explain the atrophic processes normal to old age it has naturally 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’s80 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 Gery81 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. Bechhold84 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 Marinesco85 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. Campbell86 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 Carrel87 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 Northrop88 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 Ebeling89 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 Ray90 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 Nathan91 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’s92 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 Hufeland93 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, Biedl95 expresses much the same view in referring old age to a disturbance of the endocrine balance, and Berman96 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.

Lydston97 implanted testes from boys recently dead into men with atrophied or destroyed testes and reported improvement. Stanley and Kelker98 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. Stanley99 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 Gilford100); 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 Ancel101 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 Bormann102 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. Nathan104 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. Sand105), though Blair Bell106 and Sternberg107 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 Aron109 as two different interstitial glands), and that they are present in extreme old age; Retterer110 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’s111 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 Benjamin113 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 (Benjamin113), 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: Simmonds114 and Tiedje115 have failed to confirm the occurrence of the changes in the testes after vasectomy; and Romeis116 and Marinesco117 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 published119 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’s120 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 Frank121 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 Ribbert124 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.

That intestinal toxaemia due to stasis has a very important influence in producing disease cannot be doubted, and Sir Arbuthnot Lane126 has brought this prominently to our notice; while clothing in modern language the old ideas of the primae viae he recalls to our memory Abernethy’s127 panacea for many ills of the flesh, namely a blue pill at night followed by a mixture of gentian and senna in the morning.

Among his collaborators Mr. Ernest Clarke128 has insisted on the premature ageing of persons with intestinal stasis. From the analogy of syphilis, alcoholism, and other intoxications, which may produce degenerative changes simulating those found in old age, the hypothesis of intestinal toxaemia gains a certain amount of support, and it may not be so easy to exclude the agency of intestinal toxaemia as in the case of syphilis and some intoxications. But intestinal toxaemia may, as far as can be judged, be absent in healthy old age, and conversely be present in early life without causing the phenomena of old age. Further objections have been raised:—why should intestinal toxins be harmless for 40 or 50 years and then exert such a serious influence? why should women who are more subject than men to constipation be more long-lived; and that in constipated persons the faeces, as shown by Schmidt and Strasburger, contain fewer living bacteria than in health.129

As applied to normal old age and death this hypothesis is pathological and therefore has rather failed to interest those who are working at the biological aspect. Perhaps the most that can be safely concluded in balancing the pathological and biological arguments is that while Metchnikoff’s view may be partially true it does not account for all senile changes, and that normal old age or senescence cannot be regarded as the result of toxins absorbed from the alimentary canal.

Old Age of Cells and Carcinoma

The relation between ageing of the cells on the one hand and the development of carcinoma on the other hand is a subject of great interest. According to Karl Pearson’s130 statistical enquiry the incidence of carcinoma reaches its maximum at the age of 46 years in women and 56 years in men; Lazarus-Barlow131 concluded that the range of years over which cancer is likely to occur is practically the same in the two sexes, namely 46 to 64, and that among 4659 cases of malignant disease there were only 35, or 0·7 per cent, over 80 years of age.132 The cancer age, therefore, coincides with the waning of maturity and the onset of old age; that carcinoma is rare in very old persons is also shown by the occurrence of one case only among 71 centenarians collected by Sir George Humphry. Laurent133 considered that whereas longevity depends on a condition of vital equilibrium, the development of cancer is due to a want of this equilibrium, to a state of anarchy, and that the factors disposing to orderly vitality are conducive to longevity and antagonistic to the development of new growth. The reason why malignant growths are prone to appear with the onset of old age has naturally been the subject of much debate. According to Thiersch degeneration lessens the controlling influence normally exerted by connective tissue on epithelium, the inherent proliferative capacity of which then runs riot. Ribbert believed that from loss of resistance or diminution of surface tension in the connective tissues post-natal “rests” of epithelium were produced as the result of irritation and that these displaced cells then grew because there was no controlling opposition. Adami suggested a reversion of the highly specialized epithelial cells to a simpler form with powers of proliferation, the cumulative habit of growth taking the place of the habit of work, and practically anticipated the more modern view. According to Hastings Gilford134 malignant disease is a premature cell senility and the result of the partial reversion of immature or adult cells to an embryonic or quasi-embryonic state. From a study of senescence in dogs Goodpasture135 concludes that degenerative changes in the cells lead not only to death of some cells but to dedifferentiation of others, which, becoming simpler in structure and function, recover their juvenile power of growth in varying degrees, and that hence metaplasia and tumour growths occur as accidents of commencing old age. A little later Oertel136 insisted on his view that cancer is not an embryonic reversion or a specific change in the cell but a phenomenon of senescence—a degenerative proliferation depending upon disturbances in the nucleus plasma relations, specifically upon the loss of nuclear chromosomes; from age or degeneration the tumour cell loses the higher functional chromosomes and retains the genetically older and more resistant ones controlling reproduction and vegetative activities; thus there arises a race of cells without the differentiation of undegenerated cells.

These various expressions of opinion would justify the conclusion that with the onset of old age the degenerative processes in the cells lead to the production of less specialized cells which have the compensating property of more vigorous growth, and that in certain circumstances, one of which is very probably a diminished power of resistance on the part of the surrounding tissues and another, and very important one, irritation in some form or another, riotous proliferation of the cells invades the adjacent parts. That the conditions necessary are usually local is strongly suggested by the appearance of the new growth at one spot only and by the frequent absence of recurrence after free removal. There may be a premature local senescence of the tissues, just as there is premature old age of the body generally, and this would explain the exceptional occurrence of malignant disease in early life or long before the usual time.