The Prolongation of Life: Optimistic Studies. Élie Metchnikoff
my interpretation. For several years M. Marinesco8 has attacked my theory of the atrophy of the nerve-cells in old age. In the first place, he has stated that in old people, and even if these are very old, it is rare to find phagocytes surrounding and devouring the cells of the brain. In support of this contention, he has been good enough to send me two preparations made from the brains of two very old persons. After careful examination I was convinced that my opponent had been inexact. In the brain of the two centenarians (one of whom died at the age of 117 years) there were very many nerve-cells surrounded by phagocytes and in process of being destroyed by them. It happened, however, that as the sections were very weakly stained, it was more difficult to observe the facts than in the preparations upon which I had made my own observations. I have already recorded this fact in the second and third French editions of the “Nature of Man.”
Without taking notice of my reply, M. Marinesco has published another criticism of my theory in an article9 entitled “Histological Investigations into the Mechanism of Senility.” In that work, although he himself had invented the designation “neuronophag” for a phagocyte that devours nerve-cells, he denies the existence of such a power. He thinks that nerve-cells atrophy independently of the cells that surround them. The latter, the so-called neuronophags, only contribute to the atrophy inasmuch as they press against the nerve-cells and deprive them of nutrition. He is confident that the constituent parts of nerve-cells are never found in the neuronophags. There is no question of phagocytosis, of the existence of cells that devour their neighbours.
M. Léri has taken a similar view in a Report on the Senile Brain10 presented to a recent congress of alienists and neurologists. According to him “the nuclei which surround some of the atrophying nerve-cells do not play the part of neuronophags.” In his monograph “La Neuronophagie,”11 M. Sand elaborates the same view. He relies on his observation that “neuronophags are usually either devoid of protoplasm or display only a very thin layer of it. They never exhibit protoplasmic outgrowths, and they never have granules in their cellular bodies (p. 86).” Still more recently MM. Laignel-Lavastine and Voisin12 have taken the same view, maintaining that the neuronophags do not display phagocytosis.
Although I cannot undertake here to give a detailed reply to the arguments of my critics, I may point out a fallacy that vitiates their reasoning. The study of the intimate structure of nervous tissue involves the treatment of that very delicate substance by numerous active reagents. It is extremely important not to forget the possibility of alterations which may be produced in the processes of preparation and which are extremely difficult to avoid. A glance at the figures given by my critics shows me that the neuronophags in their preparations had been subjected to violent treatment. When M. Léri speaks of “the nuclei which surround some of the nerve-cells,” and M. Sand of “cells without protoplasm,” it is clear that they had been observing cells destroyed by the processes of the laboratory. The illustrations in the memoir of M. Marinesco show that in his preparations, too, the neuronophags had been very greatly altered.
It is well known that nuclei do not exist free in tissues, and that when they appear devoid of protoplasm, there has been some defect in the technical methods of preparing them for examination. As a matter of fact, neuronophags do not consist of nuclei with at the most a pellicle of protoplasm; like other cells, they have protoplasmic bodies which, however, are frequently destroyed by the violent processes of histological preparation.
The arguments of my critics recall to me the words of a medical student, who, on being asked to describe the microbe of tuberculosis, said that it was a little red bacillus. The bacillus in question, like most bacilli, is colourless, but it is usual to stain it so that it may be visible under the microscope. The student, knowing it only in particular preparations, had a false idea of its appearance.
In well-made preparations, neuronophags are typical cells with abundant protoplasm. When they have been preserved by a process that does not dissolve their contents, they show granules like those found in nerve-cells.
To study neuronophagy, M. Manouélian,13 in the laboratory of the Pasteur Institute in Paris, set himself to improve the technical methods of preparation. He succeeded in showing first that in the destruction of nerve-cells that occurs in cases of hydrophobia, the contents of these cells are absorbed by the surrounding neuronophags. “My observations on the cerebro-spinal ganglia of human cases of hydrophobia,” he wrote, “show clearly that the macrophags act as phagocytes of the nerve-cells.” “Most of the cells in the nerve-ganglia contain yellow, brown, and black pigmented granules, usually united in small masses. What becomes of these granulations on the destruction and disappearance of the nerve-cell? If, as M. Marinesco has it, there is no phagocytosis by the surrounding cells, but merely a mechanical interference, then the granules, on the destruction of the nerve-cells that contained them, should be found lying in the interstitial tissue. But this does not happen. The granules are ingested by cells which are true macrophags.”
By the aid of a very delicate mode of preparation, M. Manouélian has shown that in the case of senile brains the granules of the nerve-cells are absorbed by neuronophags. I have myself studied M. Manouélian’s preparations and can testify to the accuracy of his observations (Figs. 6 and 7).
Doubt is no longer possible. In senile degeneration the nerve-cells are surrounded by neuronophags which absorb their contents and bring about more or less complete atrophy. It has been supposed that in order to devour their contents, the neuronophags must penetrate the nerve-cells, and such an event has rarely been seen. But it is well known, the phagocytosis of red blood corpuscles being a typical instance, that to absorb a cell a phagocyte does not necessarily engulf it bodily or penetrate it, but may gradually denude it of its contents merely by resting in contact with it.
There has been some discussion as to the condition of nerve-cells which are on the point of being devoured by neuronophags. It has been noticed that such cells may display a considerable amount of degeneration without being devoured, whilst, on the other hand, cells apparently normal have been found undergoing phagocytosis. As I cannot state definitely what are the conditions that induce the phagocytosis of nerve-cells, I shall not attempt a discussion of the problem.
Although the destruction of nerve-cells by neuronophags is a general occurrence in senile brains, one may conceive of cases where this does not occur. And so, in old people who have preserved their faculties, it may well be that the neuronophags have refrained from attacking the nerve-cells. But as such instances are rare, so also phagocytosis is usually found in senile brains, and I cannot accept M. Sand’s denial of its existence, based on his study of two cases.
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| Fig. 6. | Fig. 7. |
| FIGS. 6. & 7.—Two nerve-cells from the cortex of the brain of an old dog aged fifteen years. The neuronophags surrounding the nerve-cells contain numerous granulations. (From preparations made by M. Manouélian.) | |
The general result of my investigation into the criticisms that have been published on this matter has confirmed me in my belief that neuronophagy plays a most important part in senescence, and recent observations that I have made with M. Weinberg have completely supported this view.
The bleaching of hair and the atrophy of the brain in old age thus furnish important arguments against the view that senescence is the result of arrest of the reproductive powers of cells. Hairs grow old and become white without ceasing to grow. The cessation of the power of reproduction cannot be the cause of the senescence of brain-cells, for these cells do not reproduce even in youth.
III
MECHANISM OF SENILITY