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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.”