Chapter IV: Introduction (2)

In addition to the _joie de vivre_ a happy disposition that thinketh no evil, has no jealous suspicions, and is free from the tendency to worry has an important influence in keeping the mind and body young. The power of detachment from work and anxieties, as if the mind were fitted with thought-tight compartments, is a valuable asset in maintaining vitality unimpaired; this was a trait in Gladstone and Kitchener.

Professional men who retain their offices as in the Church, the Civil Government, the Bar, tend to live longer than business men who retire to leisured ease after a strenuous struggle. B. Yeo’s[70] analysis of 42 Bishops and Deans, 49 Judges, and 188 Peers, showed that in all three classes the average duration of life was practically the same, namely, 72 years. Among churchmen mention may be made of Cardinal de Salis (110), Gregory IX. (100), Abbé Maignon (100), Martin Routh (100), for 63 years President of Magdalen College, Oxford, thus surpassing the more modern instance of Edward Atkinson, aged 96 years, for 59 of which he was Master of Clare, but not that of Laurence Chaderton (1536–1640) who, after being Master of Christ’s College, Cambridge, with great success for 38 years, survived for 18 years and became a centenarian. There are some remarkable examples of artists retaining an active life to a very advanced age, such as Titian, Giovanni Bellini, Michael Angelo, Sidney Cooper. Politics often keep men busy and active to an advanced age, and the names of Palmerston, Brougham, Lyndhurst, the octogenarian premiers Gladstone and Clemenceau, Strathcona, Sir Charles Tupper naturally come to one’s mind. In the legal profession Chief Justices and Judges can retain their seats and so keep up their vigour long past what is regarded in some walks of life as the retiring age. Sir Edward Coke (82), Lord Mansfield (89), Lord Brampton (90), Lord St. Leonards (93), and Lord Halsbury (97), are examples in point. Within recent years there have been two octogenarian Lord Mayors of London, Sir Thomas Crosby (in 1911), and Sir John James Baddeley (1921); the first created a record by being the first medical man to hold this office, and Sir John Baddeley celebrated his year of Mayoralty by bringing out a beautiful historical account of Cripplegate.

FIG. 9.--Sir Henry Alfred Pitman (1808–1908), M.D., Camb.,
F.R.C.P., Registrar of the Royal College of Physicians of
London, 1858–1889.

From portrait in the Royal College of Physicians of London, painted in 1886 by W. W. Ouless, R.A.]

From the inevitable exposure to infection and worry the medical fraternity is generally considered to rank low in the professions as regards longevity, but it is easy to point to exceptions especially among those whose mental vigour made them prominent in their own and in one instance for all time. Hippocrates is variously stated to have died at the ages of 85, 90, 104, or 106 years with the words “I leave behind me two great physicians, temperance and frugality.”[71] I have references to 43 medical centenarians for 18 of which, including the record of W. G. Meade, physician at Tunbridge Wells and buried at Ware, Herts, in November 1652, aged 148¾ years, I am indebted to my friend Mr. R. R. James. The only one that I knew personally was Sir Henry Pitman, for 31 years (1858–89) and until his 82nd year Registrar of the Royal College of Physicians of London. Among the others Dr. de Bossy of Paris may be mentioned as the son of a centenarian. From analysis of 2113 eminent medical men Drinkwater[72] found that the average age was 67 years, or considerably above the average age of the male population over 21 years, which was estimated at 59 years, and that 627 or nearly a third of them all were between 71 and 80 years of age.

But the examples given of mental activity late in life, and they could easily be multiplied,[73] are exceptions to the rule that the majority of men begin to fail in their work between 60 and 70. This no doubt is because most septuagenarians suffer in greater or less degree from pathological old age. In the case of the healthy vigorous man enforced retirement at the age of 65 or 70 is not to the advantage of either the retiring victim or the community, for it restricts his opportunities for production and useful activities guided by ripe experience. To quote examples of epoch-making work done by men long past the age when the majority have lost originality, initiative, and elasticity of mind: Galileo, Newton, Charles Darwin, Sophocles, Voltaire, Molière, Goethe, Michael Angelo, and Titian, made original and lasting contributions to science, literature, and art long after fifty. Morgagni’s famous _De Sedibus et Causis Morborum_, brought out when he was 80, and the Commentaries of W. Heberden (aged 91), published posthumously, represent the accumulation of many years and so cannot be fairly quoted as examples of ability persisting into late life. Rules and regulations must, however, be based on what is best for the majority and hence, though the exceptions are prominent and regrettable, the age limit of 65 to 70 must at present be accepted as generally advisable for otherwise permanent appointments.

Although functional activity maintains the tissues in a state of health, it is not an infallible panacea for the prolongation of life; in the first place the danger of overwork and excessive fatigue must be borne in mind. While the attractive suggestion that excessive functional activity leading to extreme hypertrophy may exhaust the vitality of the tissues and lead to atrophy, may not be borne out by the examples quoted in its favour, such as the occupational neuroses and atrophy of the upper arm muscles in hammermen and file-cutters, there is some reason to retain a belief that this sequence of events may occur, for example in dilatation of the extremely hypertrophied hearts seen in long-continued high blood pressure, renal disease, and valvular lesions;[74] but even here the possibility of other degenerative changes, due to toxaemia, must be borne in mind. Further, functional activity while keeping the cells of the body in a healthy state depends on their structural integrity, and this in its turn is the outcome of the modifications due to environment, and possibly of the inborn lease of vitality. So that although an active life may within limits prolong life, there are many instances in which, from extrinsic pathological influences or inherent inadequacy, it fails to do so, and a man becomes unequal to the demands of his position.

PERSONAL HABITS

All experience, medical and lay, such as is embodied in Cornaro’s oft-quoted memoirs, Leonardus Lessius’s _Hygiasticon or the right course of preserving life and health until extreme old age_ (1613), George Cheyne’s _Essay of Health and Long Life_ (1724), Metchnikoff’s orthobiosis, and the Arabian proverb of the ninth century, quoted by Lacassagne,[75] that “the greatest dangers for an old man are a good cook and a young wife,” is in agreement as to the immense importance of strict moderation in indulging the appetites for the prolongation of life. The life histories of centenarians show that they have usually been small eaters, especially of meat. This is generally explained in terms of minimizing toxaemia, and it has been said that “man does not die, he kills himself” (Montaigne) and more graphically, if coarsely, that “he digs his grave with his teeth.” In some lower forms of life, such as the planarians (Child), partial starvation and the resulting reduction lead to rejuvenescence and so to the inhibition of the onset of senescence; hibernation has somewhat the same effect, though perhaps this might be partly explained as merely starvation during prolonged sleep. The question has often been raised whether partial starvation in man has any such positive influence, and unprofessional “cures” on these economical lines have not been unfashionable. It might indeed be argued that the Allen treatment of diabetes, in which starvation is followed by increased carbohydrate tolerance, depends on a certain degree of rejuvenescence. Cures consisting in purgation may act by partial starvation as well as by obviating toxaemia. After a period of starvation a normal person may become heavier than before, and his general health be improved. But in the present state of our knowledge and in the light of the dangers of starvation the further investigation in man of this problem is one that demands serious hesitation.

As to the bad influence of alcohol on longevity there can be no reasonable doubt. Alcohol is a protoplasmic poison causing degenerative changes in the cells and reducing the resistance to infection. A collective investigation undertaken by Sir Isambard Owen[76] showed that there were very few hard drinkers among the long-lived, and Sir George Humphry concluded that the characteristics of the aged included temperance; among 46 centenarians one, and among 73 men over 90 one confessed to taking too much occasionally, and out of 298 men between 80 and 90 years of age 45, or 15 per cent, were classified as taking much alcohol. That such exceptions occur is explicable by great inherent vitality. It has been said that “wine is the milk of old people,” but from his experience of the hygiene of the elderly Sir Hermann Weber was not in sympathy with this view, and he pointed out the weakness of the popular idea that the moderate enjoyment of alcohol was harmless; for so-called moderate drinking is in reality often immoderate indulgence for the individual, and most of us must have recognized from observation that long-continued though moderate use of alcohol is followed by premature deterioration. The proverb _vinum lac veneris_ and the tendency that alcohol has to lead to incontinence and so to venereal infection may be borne in mind in considering its influence on longevity. As a medicine alcohol has its occasional use, and though it may be a food it is an expensive one.

Smoking among centenarians was specially investigated by Sir George Humphry, who found that among 19 male centenarians 8 smoked much, one a little, and 10 not at all; while out of 30 female centenarians 4 smoked much, 2 moderately or little, and 24 not at all. There is no doubt that with advancing years there is commonly a relative loss of tolerance for tobacco, so that unpleasant symptoms ranging from cardiac extra-systoles, through abdominal pain, to tobacco angina, may dictate discontinuance of the habit. But a large number of old people have smoked in earlier life though subsequently non-smokers. Personal tolerance to tobacco shows great variations, and there is no doubt that well-marked symptoms may be caused by tobacco. But that moderate smoking diminishes the chance of longevity has certainly not been proved. Much discussion has taken place as to the relation between smoking and arteriosclerosis; it is true that in animals nicotine in considerably larger doses than can be absorbed by smokers, damages the arteries, and Huchard and Lazarus were convinced that it caused arteriosclerosis. Sir Clifford Allbutt,[77] after quoting the various opinions, points out that if tobacco be a cause of arterial disease, it acts very slowly, for at 45 years of age, after a quarter of a century’s exposure, the smoker’s arteries are not distinguishable from those of the abstainer’s; and he mentions the arteriosclerosis of the ancient Egyptians and of women as incidents detracting from any argument that tobacco is an important cause of arterial disease.

A large proportion of the centenarians and persons over 80 years of age collected by Sir George Humphry obeyed the adage early to rise and early to bed, and I well remember that he used to lay stress on the factor of getting up directly one woke and so denying the flesh the luxury of further sleep. Whether going to bed early and getting up early is more than an index of a life otherwise spent in accordance with the late Sir Andrew Clark’s “laws of physiological righteousness” may be questioned.

_Bodily Conformation._--Long-lived people are usually spare, obesity being rare, and, allowing for some shortening due to age, of a good average height (Humphry). It is interesting in this connexion to quote the conclusions arrived at by Robertson and Ray[78] from comparison of groups of long-lived and short-lived white mice in similar conditions. The long-lived were relatively stable, highly resistant to external disturbing factors, displaying subnormal variability and a more or less well-marked, but not invariable, tendency to early overgrowth and relative paucity of tissue accretion in late life; while the short-lived animals showed exactly the opposite features with a tendency to rapid increase of tissue in late life.

The importance of a healthy life with plenty of fresh air, sunshine, exercise, proper diet, and absence of worry hardly needs insistence. Leonard Williams[79] has epigrammatically summed up the hygiene of old age as “Fresh air, meagre fare, freedom from care.”

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’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.

That intestinal toxaemia due to stasis has a very important influence in producing disease cannot be doubted, and Sir Arbuthnot Lane[126] 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’s[127] 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 Clarke[128] 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’s[130] statistical enquiry the incidence of carcinoma reaches its maximum at the age of 46 years in women and 56 years in men; Lazarus-Barlow[131] 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. Laurent[133] 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 Gilford[134] 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 Goodpasture[135] 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 Oertel[136] 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.

VI

NORMAL STRUCTURAL CHANGES IN OLD AGE

Physiological old age, namely a process of involution and atrophy uncomplicated by superimposed pathological changes, is extremely rare; pathological processes may initiate and hurry on a condition imitating old age, and indeed the morbid changes found after death in old people commonly show the lesions of past infections in addition to those of physiological involution, and the longer life lasts the greater the probability that changes due to disease will accumulate. It is therefore difficult to determine accurately where physiological involution ends and pathological lesions begin, and there has been much confusion between physiological old age and pathological senility. It must, on the other hand, be admitted that the ideal condition of physiological involution without some definite evidence of superadded pathological change hardly ever comes before us. In fact at the best old age is almost always but relatively physiological, in other words, as Metchnikoff wrote in 1903, there is at present, from the conditions of inharmonious environment, no chance of a really physiological old age and death for mankind. But the view that old age is invariably the accumulated product of multiple injuries due to infection and poisons, or that it is due to arteriosclerosis (Boerhaave, Haller, Demange) is an entirely different proposition and does not fit in with biological knowledge. While fully recognizing the difficulties an attempt may be made to tabulate the natural changes accompanying and responsible for old age, and to contrast them with the pathological changes commonly complicating the normal structural involution of the human body.

The general atrophy of old age, as grossly shown by loss of weight, does not proceed equally in all parts of the body. The supporting fibrous tissues of the body and organs certainly atrophy less than the nobler, because actively functional, cells of the organs; it is difficult to estimate the atrophy of the fibrous tissues, for from shrinkage of the parenchyma of organs and of muscles the fibrous framework stands out in greater prominence. Some proliferation or replacement fibrosis follows atrophy of the nobler tissues, and pathologically infection may cause fibrosis. But that the fibrous tissue does to some extent share in the general atrophy is rendered probable on the analogy of the change in the allied tissue of bone which undergoes rarefaction and thinning. The subcutaneous and perivisceral stores of fat diminish out of proportion to the fibrous supporting tissues around them. The place of the fat in the fat cells may be taken by fluid--serous atrophy--or the cells may simply revert to the condition of connective tissue cells. In passing it may be pointed out that it is curious that with the diminished metabolism of old age the stores of fat are not increased as they are in similar circumstances in adult life; Is it due to a widespread atrophy of the connective tissue cells that store fat? If so, an accumulation of fat in the liver might be expected, but this is not so. Possibly it is the result of deficient assimilation. The heart, as Councilman[137] has shown, is on the whole better preserved than the other organs; but it might well be argued that the existence of such a cardiac condition is a determining factor in the attainment of advanced age.

_The skin_ is dry, thin, smooth, glossy from atrophy, inelastic like parchment, and is wrinkled from degeneration and disappearance of the elastic tissue, subcutaneous fat and muscular fibre. These changes are most advanced on the face, especially the forehead, and backs of the hands from exposure. The degeneration of the elastic fibres, recently studied by Kissmeyer and With,[138] gives a characteristic mesh-like appearance, depending on the rigid wrinkles, to the skin, which takes a yellow tint. The ivory pallor and coldness are due to the diminution in the capillaries; the skin may show areas of pigmentation and leucodermia--changes described by Sir Lenthal Cheatle as due to the wear and tear of life (biotripsy); in a woman aged 93 Salimbeni and Gery described almost complete disappearance of the papillae and of the collagen fibres. The pigmentation has been regarded as a means of protection, for there is a relation between it and malignant disease, the latter being prone to occur when pigmentation fails (Pringle[139]). These atrophic changes are far commoner on the backs than on the palms of the hands, and it is noteworthy that among Cheatle’s[140] 200 collected cases of malignant disease of the hand there was one only on the palm. The subcutaneous fat is diminished in amount, which is regarded by Sir Arbuthnot Lane, though not with any special reference to old age, as one of the many results of colonic toxaemia. The yellow fat contains excess of cholesterol. There is diminished secretion by the sweat and sebaceous glands, and from this cause and the diminished vascularity there is less loss of heat to correspond with the slower metabolism.

_Hair._--Greying or whitening of the hair occurs commonly in old age, but not universally for some centenarians have retained the natural colour of the hair; coarse jet-black hair is specially prone to whiten early. The change in colour has been ascribed by Metchnikoff to the action of phagocytes (chromophages) which invade the roots of the hairs and carry off the pigment granules. Like the arcus senilis it may occur quite early in life and without any other indication of age, and is often hereditary; as the sage of Norwich wrote, “Hairs make fallible Predictions, and many Temples early Gray have outlived the Psalmist’s Period.”[141] Lord Bacon[142] indeed said, “Hasty gray hairs, without baldness, is a token of long time; contrarily, if they be accompanied by baldness.” But baldness is often due to seborrhoea and so only secondarily connected with advanced age. In some rare instances the hair already grey or white has been known to regain its normal colour; the late Sir Charles Cameron[143] recorded this event in his own life after an accident confining him to bed for some months in his eightieth year, and refers to the hair of a man aged 90 years returning to its original brown colour; cases were also reported by Graves.[144] Velasquez de Tarente[145] recorded an abbess who after an illness which promised to be fatal in her hundredth year had a crop of brown hair, and, like Sir Charles Cameron, put on weight. Four other cases are given by Sir John Sinclair[146] in persons aged 80, 104, 105, and 114 years. Baldness may be definitely due to thyroid insufficiency and not to atrophy of the hair follicles and sebaceous glands.

A pensioner aged 75, whom I saw with Major R. J. C. Thompson,
in the Royal Hospital, Chelsea, with baldness and a grey
beard, was given thyroid extract, as he was thought to
have hypothyroidism; his general condition then improved
wonderfully, and his scalp became covered with dark brown hair
which had to be cut at intervals. Parkinsonian tremor was
rather more obvious during the first six months that he was on
thyroid treatment.

The hair of the body may become scanty and lose its tendency to curl. Excessive growth of hair (hypertrichosis) in women after the menopause is an indication of disordered endocrine balance (loss of ovarian internal secretion?) and is only so far an accompaniment of age; it may be seen in comparatively young women from various causes.

_The nails_ are often longitudinally ridged, brittle, hard, and thickened; but onychogryphosis is rather the result of neglect or of disease than solely of old age.

_The brain_ as a natural result of atrophy becomes lighter; Boyd’s[147] tables show that the male brain is 3 oz., and the female brain 4 oz., lighter in persons over 80 years of age than in the decade 20 to 30. The convolutions, therefore, become separated and the amount of cerebrospinal fluid greater. The atrophy is not uniform, being less in the posterior third than in the anterior two-thirds. The nerve cells become smaller, pigmented, and degenerate. The brain is said by Cerlette to be affected by a process special to old age--miliary necroses scattered over the cortex and associated with changes in the small arteries which show remarkable knots; a condition which suggests a pathological softening secondary to arteriosclerosis, especially as the change does not come on constantly at a definite age period. Cavities with thickened walls, possibly due to miliary haemorrhages, or to softening around the vessels are also described. Metchnikoff’s description of phagocytic destruction of the nerve cells by macrophages has been seriously questioned and thought to be based on erroneous observation, the glia cells being regarded as macrophages (Marinesco).

The spinal cord shows an increased number of amyloid bodies, some diffuse sclerosis, often obliteration, by epithelial proliferation, of the central canal, and atrophy with pigmentation of the nerve cells, especially in the anterior cornua. The membranes may contain small calcareous plaques.

_The arcus senilis_, due to infiltration with fats, especially cholesterol and lipochrome, and to degeneration of elastic tissue at the periphery of the cornea, is often associated with arteriosclerosis (Monauni[148]). It is not a necessary accompaniment of age; among 321 persons over 80 years of age, it was absent in 114, or 35·5 per cent (Humphry); and it is well known that like grey hair, it may occur in those young in years. Nascher,[149] the author of _Geriatrics_, had an arcus senilis as a schoolboy. Rigidity and flattening of the crystalline lens lead to presbyopia, which may be premature and due to toxaemia, among the causes of which Ernest Clarke[150] gives intestinal toxaemia a high place. The power of accommodation is also impaired by weakness of the ciliary muscle brought about in the same way.

_Skeleton._--The atrophy characteristic of senescence is well shown in the fixed tissues of the bony skeleton. Though the bones do not as a rule alter materially in size or shape, they do so markedly in substance from rarefaction and absorption, the latter taking place mainly from the inside of the bones and especially the cancellous tissue, the medullary cavity and the Haversian canals becoming larger (senile osteoporosis). Hence fractures near the joints, particularly intracapsular fracture of the neck of the femur, are favoured. The absorption of the alveolar border of the jaw is intimately connected with the loss of the teeth, and brings the mental foramen to the top of the edentulous mandible. The angle of the jaw at the junction of the body and the ramus now opens out and comes to resemble that of an infant. It is often stated that the angle of junction of the neck and shaft of the femur becomes less, more of a right angle, but Humphry regarded this as exceptional.