Читать книгу The Prolongation of Life: Optimistic Studies - Élie Metchnikoff - Страница 8

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Action of the macrophags in destroying the higher cells—Senile degeneration of muscular fibres—Atrophy of the skeleton—Atheroma and arterial sclerosis—Theory that old age is due to alteration in the vascular glands—Organic tissues that resist phagocytosis

The instances which I have selected in attempting to describe the mechanism of senescence of the tissues are not the only cases in which the importance of phagocytosis is evident. The blanching of hair is due to the destructive agency of chromophags; in atrophy of the brain neuronophags destroy the higher nerve-cells. In addition to these instances of phagocytosis, in which the active agents belong to the category of macrophags, there are many other devouring cells, adrift in the tissues of the aged, and ready to cause destruction of other cells of the higher type. The phagocytic action is not so manifest as in the case of infectious diseases, partly because it is the method of macrophags to absorb the contents of the higher cells extremely slowly. The mode of action is well seen in the atrophy of an egg-cell (Fig. 8), where the surrounding macrophags gradually seize hold of the granules within it and carry these off. As the process goes on, the ovum becomes reduced to a shapeless mass, and finally leaves only a few fragments, or disappears completely. M. Matchinsky14 has studied the series of events in my laboratory, and I am myself well assured of the importance of the action of macrophags in the atrophy of the ovary.

Fig. 8.—Ovum of a Bitch in process of destruction by Phagocytes, which are full of fatty granules.

(After M. Matchinsky.)

The phenomena of atrophy in general and of senile decay afford other cases of tissue destruction in which the phagocytic character of the process is more modified and obscure than in nerve-cells and ova.

It is well known that progressive muscular debility is an accompaniment of old age. Physical work is seldom given to men over sixty years of age, as it is notorious that they are less capable of it. Their muscular movements are feebler and soon bring on fatigue; their actions are slow and painful. Even old men whose mental vigour is unimpaired admit their muscular weakness. The physical correlate of this condition is an actual atrophy of the muscles, and has for long been known to observers. More than half a century ago, Kölliker,15 one of the founders of histology, devoted some attention to this matter, and described the senile modification of muscular tissue in the following words:—“In old age there is a true atrophy of the muscles. The fibres are much more slender; there are deposited in their substance numerous yellow or brown granules and many globular nuclei. These nuclei are frequently arranged in longitudinal series and present such signs of active division as are found in embryonic tissue.”

Other investigators afterwards made similar observations. Vulpian16 and Douaud17 have stated that a multiplication of nuclei takes places in the atrophying muscles of the old.

As the senile degeneration of muscular tissue appeared to be important in my study of the mechanism of senescence, M. Weinberg and I examined several cases of muscular atrophy in old human beings and lower animals. We were able to recognise the phenomena observed by our predecessors. In senile atrophy the muscular fibres contain many nuclei, and these, increasing rapidly, bring about an almost complete disappearance of the contractile substance (Fig. 9). The fibres preserve their striation for a certain time but eventually lose it and appear to contain an amorphous mass with numerous, rapidly multiplying nuclei.

Fig. 9.—Degeneration of striated muscle Fibres from the auricular muscle of a man aged 87 years.

(From a preparation made by Dr. Weinberg.)

The investigators who had recorded these facts thought of them only as curious. It is plain, in the first place, however, that this remarkable and rapid multiplication is a proof that senile atrophy is not due to failure of cell proliferation, although the latter has frequently been suggested as the mechanism of senescence. In muscular atrophy, cell multiplication, so far from failing, greatly increases. We may add muscular atrophy to the blanching of hair and the decay of nerve-cells as another instance showing that senile degeneration is not the result of cells ceasing to be able to multiply. Just as in the atrophy of the brain there is an increase in the volume of neuroglœa, the substance in which the neuronophags are found, so also in the atrophy of the muscles there is an increase of muscular nuclei. Along with the increase of nuclei, however, there is an increase of the protoplasmic substance of the fibres known as sarcoplasm. The latter replaces the myoplasm, the specific striated substance of muscles, by a process which must be regarded as parallel with phagocytosis. In a normal muscle the two substances and the sarcoplasmic nuclei are in equilibrium, but in old age the sarcoplasm and its nuclei increase at the expense of the myoplasm. The equilibrium is destroyed with the result that the muscular power is weakened. In these conditions the sarcoplasm acts phagocytically with regard to the myoplasm, just as the chromophag becomes the phagocyte of the pigment of the hair, or the neuronophag devours the nerve-cell.

The investigation of other cases of muscular atrophy, as, for instance, that of the caudal muscles of frog-tadpoles, confirms the significance of the process that I have observed in old age. In the two cases, what takes place is the destruction of the contractile material of the muscles by myophags, a special kind of phagocyte.

It is one of the curiosities of senile atrophy that whilst there is hardening or sclerosis of so many organs, the skeleton, the most solid part of our frame-work, becomes less dense, so that the bones are friable, the condition often leading to serious accidents in old people. The bones become porous, and lose weight. It is difficult to believe that macrophags, although they destroy softer elements such as nerve-cells or muscle fibres, can be able to gnaw through a hard material like bone impregnated with mineral salts. As a matter of fact, the mechanism of bone atrophy must be placed in a different category from the phagocytosis of other organs. It is brought about, however, by the agency of cells very like some of the macrophags. These cells contain many nuclei, and are known as osteoclasts. They form round about the bony lamellæ and lead to their destruction, but are incapable of breaking off fragments of bone and dissolving them in their interiors. Although the intimate mechanism of this destructive action is not thoroughly understood, it seems probable that the cells secrete some acid which softens bone by dissolving the lime salts. The process can be observed in the different varieties of caries of the bone, and in the bony atrophy of old age as is represented in Fig. 10.

By the action of the osteoclasts, which themselves are macrophags, part of the lime in the skeleton is dissolved during old age and passes into the general circulation. This is probably a source of the lime which is deposited so readily in the different tissues of old people. Whilst the bones become lighter, the cartilages become bony, the inter-vertebrate discs in particular becoming impregnated with salts, so that the well-known senile malformation of the backbone is produced.

Fig. 10.—Destruction by osteoclasts of bony matter in the sternum of a man aged 81 years.

(From a preparation made by Dr. Weinberg.)

As a result of this displacement of lime in old age, the blood-vessels become modified in a distinctive fashion. Atheroma of the arteries is not invariable in old people, but it occurs extremely frequently. In this form of degeneration, lime salts are deposited in the walls of the cells, so that they become hard and friable. Several others, among whom I may mention Durand-Fardel and Sauvage, have laid stress on the coincidence of atheromatous lesions of the arteries and senile degeneration of the bones. The relations between the two alterations are very evident in the skull; the meningeal artery becomes sinuous and atheromatous, and the grooves on the inner side of the bones of the skull in which it runs, flatten out, and become larger because of other malformations.18

There is no disharmony in the nature of old people so striking as this transference of the lime salts from the skeleton to the blood-vessels, producing as it does a dangerous softening of the former, and a hardening of the latter that interferes with their function of carrying nutrition to the organs. It is the manifestation of an extraordinary disturbance of the properties of the cells that compose the body. The atheromatous condition of the arteries is closely linked with arterial sclerosis, an affection which is very common, although not constant, in the aged. The whole question of these vascular alterations is extremely complex, and before it can be cleared up, a number of special investigations must be made.

Probably diseases of the arteries of different kinds, and arising from different causes, are grouped under the terms atheroma and sclerosis. In some cases the lesions are inflammatory and are due to the poisons of microbes. An example of such an origin is the case of syphilitic sclerosis, in which the specific microbes (spirilla of Schaudinn) lead to precocious senescence. In other cases the arteries show phenomena of degeneration resulting in the formation of calcareous platelets which interfere with the circulation of the blood.

Investigations which have been made in recent years have led to very interesting results concerning the origin of atheroma of the arteries. In most cases, attempts to produce such lesions of the arteries by experimental methods have not succeeded, but M. Josué19 has been able to produce true arterial atheroma in rabbits by injecting into them adrenaline, the secretion of the supra-renal capsules.

This experiment has been repeated many times and is now well known. Later on, M. Boveri20 obtained a similar result by injecting nicotine, the poison of tobacco. It is obvious, therefore, that amongst the arterial diseases which play so great a part in senescence, some are chronic inflammations produced by microbes, whilst others are brought about by poisons introduced from without.

It is easy to understand, therefore, why these diseases of the arteries are not always present in old age, although they are very common.

The part played by the secretion of the supra-renal glands in the production of arterial disease has brought renewed attention to a theory which supposed that certain glandular organs in the body play a preponderating part in senile degeneration. Dr. Lorand21 in particular has argued that “senility is a morbid process due to the degeneration of the thyroid gland and of other ductless glands which normally regulate the nutrition of the body.” It has long been noticed that persons affected with myxodema, as a result of the degeneration of the thyroid gland, look like very old people. Everyone who has seen the cretins in Savoy, Switzerland, or the Tyrol, must have noticed the aged appearance of these victims, although very often they are quite young. The condition of cretinism, with its profound bodily changes, is the result of degeneration of the thyroid gland. On the other hand, it is well known that in old people the thyroid and the supra-renals frequently show cystic degeneration. It is quite probable, therefore, that these so-called vascular glands have their share in producing senility. Many facts show that they destroy certain poisons which have entered the body, and it is easy to see that, if they have become functionless, the tissues are threatened with poisoning. It does not follow, however, that their action in producing senility is exclusive, or even preponderating. M. Weinberg, at the Pasteur Institute, made special investigations on this point, and found that the thyroid gland and the supra-renal capsules were almost invariably normal in old animals (cat, dog, horse), although the latter showed unmistakable signs of senility. Similarly in an old man of 80 years, who died from pneumonia, the thyroid gland was quite normal.

It must not be forgotten that the aged very often die from infectious diseases such as pneumonia, tuberculosis, and erysipelas. In these diseases the vascular glands generally, and the thyroid gland in particular, are very often affected, with the result that what is due to infection has been set down as a symptom of old age.22

Although the appearance of patients from whom the thyroid gland has been removed, or in whom it has degenerated spontaneously, recalls that of old people, it is possible to exaggerate the similarity. In the masterly accounts of such unfortunates, recently compiled by the well-known surgeon Kocher23 there are many points which are characteristic, without being typical, of old people.

Oedema of the skin which characterises thyroid patients is by no means usual in old age. The loss of hair, normal in the patients, is not a character of old age. In myxedematous women, menstruation is very active; it ceases in old women. The great muscular development of myxedematous patients distinguishes them from old people.

Physiological investigation does not support the existence of any strong affinity between old age and affection of the thyroid gland. It is known that removal of the thyroid is followed by cachexia only in young subjects, MM. Bourneville and Bricon24 having shown that the tendency to cachexia after extirpation of the thyroid ceases almost abruptly at the age of thirty. That age may be taken as the limit of youth, of the time when growth is vigorous and the function of the thyroid most active. Cases of cachexia, where the thyroid gland has been removed in old persons from fifty to seventy, are very rare.

Rodents (rats, rabbits) support the removal of the thyroid extremely well, without signs of cachexia, although these are normally short-lived creatures. According to Horsley25 extirpation of the thyroid is not followed by cachexia in birds or rodents and is followed by it only very slowly in ruminants and horses; it produces the condition invariably but slightly in man and monkeys and extremely seriously in carnivora. If this series be compared with the information given in the next section of this volume on the relative ages which the animals in question attain, it will be seen that there is no correspondence.

In short, whilst I do not deny that the vascular glands may take a share in the causation of senility, in so far as they are destroyers of poisons, I cannot agree with the theory of Dr. Lorand.

I think it indubitable that in senescence the most active factor is some alteration in the higher cells of the body, accompanied by a destruction of these by macrophags which gradually usurp the places of the higher elements and replace them by fibrous tissue. Such a process affects the organs of secretion (kidneys), the reproductive organs, and in a modified form the skin, the mucous membranes, and the skeleton. The testes are amongst the organs which resist invasion by macrophags. Fig. 11.—Testis tissue from a dog aged twenty-two years. (From a preparation made by Dr. Weinberg.) I have already given an example (“The Nature of Man,” p. 98) of an old man of 94 in whom active spermatozoa were produced. I know of a similar case, the age being 103 years. Such cases are not rare, and not only in old men, but in old animals, the testes continue to be active. Dr. Weinberg and I have investigated these organs in a dog which died at the age of 22 years after several years of pronounced senility. Many of the organs of the animal exhibited serious invasions by macrophags but the testes were extremely active, the cells being in free proliferation and producing abundant spermatozoa (Fig. 11). In harmony with this condition of the sexual organs, the sexual instincts of the animal remained normal. We have investigated another dog which died at the age of eighteen years. In this case the testes were cancerous and there was no possibility of the production of spermatozoa. None the less, this dog although markedly senile (Fig. 12) still showed sexual instincts until shortly before it died.

Fig. 12.—An old dog, aged eighteen years.

It is manifest that the tissues do not invariably degenerate in old age, nor do all the organs that are modified in old age show destruction by phagocytes and replacement by connective tissue. Organs which produce phagocytes, such as the spleen, the spinal marrow and the lymphatic glands, certainly show traces in old age of fibrous degeneration but remain sufficiently active to produce macrophags which destroy the higher cellular elements of the body. I have frequently noticed cell division in such organs, and as an example may give the case of the bone marrow taken from a man of 81 years (Fig. 13).

The eye is an organ that is modified in old age without the action of macrophags. Cataract and the senile arc which appears as a milky ring at the edge of the cornea are frequent in old age. These modifications are due to impregnation of the parts affected by fatty matter which makes them opaque. This deposition of fat26 has been attributed to defective nutrition. In most organs such fatty degeneration is followed by phagocytosis, but the cornea and the crystalline lens are exempt from this consequence for anatomical reasons. Most organs possess in addition to their higher elements a constant source of macrophags. Such a source of phagocytosis is the neuroglœa Fig. 13.—Bone marrow from the sternum of a man aged eighty-one years. (From a preparation made by Dr. Weinberg.) in nervous tissues, the sarcoplasm in muscular tissues; the bones contain osteoclasts and the liver and the kidneys are readily invaded by phagocytes from the blood. The lens and the cornea have no cells that are able to become macrophags.

Some infectious diseases bring about precocious senility. A syphilitic child is “a miniature old man, with wrinkled face, skin dull and discoloured and flabby and hanging in folds as if it were too large.”27 In such a case the active agent is the microbe of syphilis which has poisoned the child on the breast of its mother. It is no mere analogy to suppose that human senescence is the result of a slow but chronic poisoning of the organism. Such poisons, if not completely destroyed or eliminated, weaken the tissues, the functions of which become altered or enfeebled, so that, amongst other changes, there is deposition of fatty matter. The phagocytes resist the influence of invading poisons better than any of the other cells of the body and sometimes are stimulated by them. The general result of such conditions is that there comes to be a struggle between the higher cells and the phagocytes in which the latter have the advantage.

The answer to the question as to whether our senescence can be ameliorated must be approached from several points of view. This course I shall now follow.