Part 5

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.

From muscular weakness the back becomes bent and as a result the vertebrae become altered in shape. Ossification of the anterior common spinous ligament--a change analogous to rheumatoid osteophytes around the more movable joints--is an added and not uncommon change but, like calcification of the costal and laryngeal cartilages, it is a morbid process, and when advanced constitutes spondylitis deformans. The intervertebral discs undergo some loss of elasticity and atrophy, thus contributing to the loss of height. The cranial bones are usually thinned, and the parietal bones may show symmetrical or nearly symmetrical oval areas of excessive absorption of the outer and even of the inner table, so that the epicranium and the dura mater may be in contact. These areas which are close to the longitudinal fissure must not in the case of ancient skulls be mistaken for examples of early trephining. The bony sutures tend to become obliterated. Instead of thinning and loss of weight the skull, especially the vault, may show thickening and be heavier than normal--a change involving chiefly the inner surface and ascribed by Sir George Humphry to shrinkage of the brain.

Calcification of the costal and laryngeal cartilages, which have a yellow tint from fatty change, is, like a similar change in the arteries, pathological and not part of the process of senescence. Thus among 10 recorded necropsies on centenarians the costal cartilages were calcified in 2 only. Calcification of the costal cartilages interferes with the respiratory movements and was regarded by Sir George Humphry, who tested for it by estimating the elasticity perceived when gentle pressure is exerted on the lower part of the sternum, as a bad omen for the future.

_The teeth_ are usually, but not invariably, few in the aged, for care or lack of it, the accumulated effect of long-continued mechanical injuries, altered calcium metabolism, and diminished resistance to infection will necessarily influence the amount of decay. Statistics, especially Humphry’s, show that in extreme old age very few teeth are present, and it is tempting to correlate the diminished provision for mastication with the lessened need for food. Sir Isaac Newton, however, at the age of 85 was said to have lost one tooth only. The numerous reputed instances of a third dentition can be explained only by the appearance of a previously buried tooth through the atrophying gums, for a genuine third dentition would necessitate the presence of dental germs which do not exist.

_The gastro-intestinal tract_ shows atrophy of the muscular coat and its secreting glands, so that dilatation of the thin-walled, pale stomach and colon occur on less provocation than in adult life and digestion is impaired; from lack of mucous secretion combined with loss of motor vigour constipation is common. It may be added that hypertrophy of the prostate by interfering with peristalsis of the colon has been thought to cause gerontal constipation (Hollis[151]). The pancreas shows fibrotic atrophy and becomes smaller and harder. From the loss of fat and muscular atrophy visceroptosis is not uncommon.