Senescence, the Last Half of Life

by G. Stanley Hall

Physiological integration, with its increasing stability of the structural substratum, makes senescence cumulative as we go up the scale of evolution, so that it is ever less balanced or offset by rejuvenation, reproduction, or other regressive changes, as is the case with simple organisms whose life cycle consists merely of brief alternating phases of progression and regression, for the large protozoan cell about to divide is old compared with the two smaller daughter cells formed from it. Senescence is retardation and rejuvenescence is the acceleration that works by transforming, readapting, and even sloughing off old and useless structures. It will take long to modify the course of evolutionary processes that are the result of millions of years of alternating progressive and regressive changes, but not only the phenomena of rejuvenescence but “sports” and saltatory mutation, to say nothing of the findings of recent experiments showing how life and even activities of somatic cells separated from the body and given a more favorable environment may be indefinitely prolonged, point toward a vast reservoir of vitality. Thus we come to a new appreciation of the incalculable energy behind all the phenomena of animate existence and the hope is irrepressible that somehow, although we have as yet no idea how or when, we may abate or inhibit the forces that check or repress it and man may emerge into a fuller and even a longer life.

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Jacques Loeb, of the Rockefeller Institute, has devoted himself for many years, with a rare combination of great learning and originality, to problems directly or indirectly bearing upon old age and death.[175] As his studies of tropism show, he is prone to mechanical and chemical interpretations; and since science has more or less eliminated smallpox, typhoid, yellow fever, malaria, rabies, diphtheria, meningitis, etc., the citizens of scientific nations will sometime, he thinks, be guaranteed a pretty fair probability of a much longer duration of life than they now enjoy. If we define life as the sum of all those forces that resist death, which means disintegration, the latter is comparable to digestion, which transforms meat into soluble products by two ferments, pepsin in the stomach and trypsin in the intestine. These ferments break up the mass into molecules small enough to be absorbed by the blood, and both of them exist not merely in digestive organs but probably in all living cells. They do not destroy our body, perhaps because the coöperation of both is required to do so and this is possible only at a certain degree of acidity, which cannot be reached in the living body because respiration is constantly removing acid. Death thus really comes when respiration ceases.

Of course there is another cause of disintegration, namely, microörganisms from the air and in the intestines. During life the cells are protected by a normal membrane that is destroyed in death and then the action of the microörganisms can superpose itself upon that of digestion. Thus in man death is stopping the breath and this may be done by poison, disease, etc. The problem is whether there is any natural death, for if not we ought to be able to prolong life indefinitely. But we cannot experiment on man because neither the intestines nor respiratory tract can be kept free from microbes. A Russian, Bogdanow, solved this problem for the fly, putting its fresh eggs into bichlorid of mercury, which a few survived, with no microörganisms on the outside. These eggs were then developed on sterilized meat in sterile flasks and Guyemot raised 80 generations of fruit flies thus. Loeb himself and Northrop raised 87 generations. Their dead bodies were transferred to culture media such as are used for the growth of bacteria and more were produced thus for years. Hence fruit flies freed from infection and well fed would not entirely escape death and probably higher organisms would thus die from internal causes were external ones excluded. Eggs, for example, those of starfish, ripen and disintegrate very rapidly if not fertilized by the process of autolysis, which acts only after the egg is ripe. The fertilized egg, however, does not degenerate in the presence of oxygen but dies in its absence, so that we might say that the fertilized egg is a strict aërobe and the unfertilized, an anaërobe. The entrance of the spermatozoön saves the life of the egg.

Is natural death due to the gradual production in the body of harmful toxins or to the gradual destruction of substances required to keep up youthful vigor? If the latter, the natural duration of life would be the time necessary to complete a series of chemical reactions that would produce enough of the toxins to kill. Now, the period necessary to complete a chemical reaction diminishes rapidly when the temperature is raised, and increases when it is lowered. This time is doubled or trebled when the temperature is lowered by 10° C. The influence of temperature on the rate of these processes seems typical. If the duration of life, then, is the time required for the completion of certain chemical reactions in the body, we should expect it to be doubled or trebled when we lower the temperature. We can test this only where, as in our flies, infection is avoided. Northrop put their fresh eggs on sterilized yeast at a temperature of 0.2° C., and the higher temperatures selected were 5°, 10°, and 25°. All the flies died at nearly the same time when kept in the same temperature. The total average duration of life was 2½ days at 30° C., when nearly all of them died. At 10° C. it was 177 days. Thus heat accelerates all chemical action, and here we have the duration of life increased from 200 to 300 per cent. In man the body temperature is constant, for example, 35.5° C. whether in the tropics or the Arctic regions. If we could reduce our temperature, we might live as long as Methuselah. If we could keep the body temperature at 7.5° C. and follow the above ratio, we should live about 27 times 70 or about 1,900 years. Thus the duration of life seems to be the time required for the completion of a chemical reaction or a series of them. The latter may be the gradual accumulation of harmful products or the destruction of substances required for sustaining youth. Not only are unicellular organisms immortal and the life of all their successive generations a continuum, but a bit of cancer tumor can be transplanted to other individuals and there grow larger, and a bit from this second individual transferred to a third, and so on indefinitely; so that the same cancer cell continues to live on in successive transplantations throughout many individual lives. It has thus outlived many times the natural life of the mouse. Indeed, it seems to be able to live on indefinitely and Carrel has shown that this is true of other normal cells. Thus death may not be at all inherent in the individual cell but only be the fate of more complicated organisms in which the different types of structure depend on each other. Certain cells are able to produce substances that slowly become harmful to some vital organ or center and its collapse brings death to the whole.

In man there is no sharp limit between youth and maturity unless it be marked by puberty, but in lower forms of life it is demarcated by a metamorphosis. The tadpole, for example, becomes a frog in the third or fourth month of its life and this process can be accelerated by feeding the creature with thyroid, no matter from what animal. Gudernatsch was able to make frogs no larger than a fly. Allen showed that the tadpole with the thyroid removed can never become a frog, although it may live long and continue to grow larger than the usual tadpole; but if such aged tadpoles are fed with thyroid they promptly become frogs. Salamanders metamorphose by merely throwing off the gills and changing the skin and tail, and the Mexican axoloti maintains the tadpole form through life; but even it, when fed with thyroid, promptly metamorphoses. Schwingle induced metamorphosis in tadpoles by feeding them with a trace of inorganic iodine. Thus the duration of the tadpole stage seems to be the time required to secure a certain compound containing iodine. Insects hatched as maggots will become chrysalides and then flies, but if thyroid is fed to the maggot it accelerates the metamorphosis, although we do not know whether it is due to the accumulation or formation of definite compounds.

Loeb sought to determine whether the duration of the maggot in the larval stage could be due to temperature and he found that this had effects similar to those described above. The larval period lasted 5.8 days at 25° C. and 17.8 days at 15°. The total duration of life was 38.5 days at 25° and 123.96 at 15°, both ratios being 1 to 3. Thus the influence of temperature upon the larval period was like that which it exerted on adult life. The same effect he found in salamanders, all of which suggested to him the conclusion that the duration of life and of the larval period is really the time required for the completion of certain chemical reactions. The cessation of respiration, which means death, and alterations in circulation, which mean metamorphosis or the death of youth, are critical periods and perhaps both points are reached when a certain toxin is formed in sufficient quantity or when a necessary substance is destroyed or reduced. Thus a shortened youth can, in amphibians, be prolonged by modifying the temperature or offering the specific substance that causes metamorphosis, namely, iodine or thyroid. There is no end to the substances capable of hastening death; shall we ever find one that can prolong life?[176]

Pearl’s experiments on the fruit fly[177] show that where long- and short-lived strains are mixed, the first generation they produce is longer-lived than either parent and that for subsequent generations Mendelian laws hold even for longevity, so that there is increased vigor in the hybrid generation due to the mingling of germ plasms that are different. As to bacterial invasion, the stability and resistance of the organism is also a factor, but by rearing insects kept free from all such invasion it appears that “bacteria play but an essentially accidental rôle in determining the length of the span of life in comparison with the influence of heredity.” Pearl criticizes the conclusion of statisticians like Hersch that poverty shortens human life, despite the fact that this is perhaps the most potent single environmental factor affecting civilized man to-day. But we have no real evidence that if the conditions between the rich and poor were reversed the death rate would also be reversed. The influence of high temperature, which is known to accelerate all the metabolic processes, does not interfere with the predominant influence of heredity because it only accelerates life processes exactly in the same way that it accelerates chemical activities and the same is more or less true of the influence of the secretions of the endocrine glands.

Pearl concludes[178] that it has already been demonstrated that cells from nearly every part of the metazoan soma are potentially immortal, even in the case of tumors by transplantation, though of course not yet for such exceedingly specialized structures as hair and nails. Under artificial conditions cells from nearly all organs can be made to long outlive the body from which they are taken, just as grafts from apple trees may be passed on indefinitely to successive generations. Thus death is not a necessary inherent consequent of life in even somatic cells but “potential longevity inheres in most of the different kinds of cells for the metazoan body except those which are extremely differentiated for peculiar functions.” The special conditions under which this occurs are often very complex and differ greatly for different tissues and animals, and we shall probably know far more later of the chemico-physical conditions necessary to insure continuous life, for these studies are new, having begun barely twenty years ago. The reason that all these essential tissues are not actually immortal in multicellular animals is that the individual parts do not find in the body the conditions necessary for their continued existence, each part being dependent upon other parts. This view differs from Minot’s that there is a specific inherent lethal process going on within the cells themselves that causes senescence. Pearl concludes “that these visible cytological changes are expressive of effects, not causes, and that they are the effects of the organization of the body as a whole as a system of mutually dependent parts and not a specific inherent and inevitable cellular process. Cells in culture in vitro do not grow old. We see none of the characteristic senescent changes in them.” Thus it may be inferred that when cells show characteristic senescent changes it is because they are “reflecting in their morphology and physiology a consequence of their mutually dependent association in the body as a whole and not any necessary progressive process inherent in themselves. Thus senescence is an attribute of the multicellular body as a whole consequent upon its scheme of morphologic and dynamic organization.” The lethal process, thus, does not originate in the cells themselves. “In short, senescence is not a primary attribute of the physiological economy of cells as such.”

It has long been known, as we have seen, that unicellular organisms could go on dividing indefinitely and that germ plasm had a potential mundane immortality; but no one had suspected that highly organized and differentiated somatic cells, which had lost the power of producing the whole individual and could only produce cells of their own special tissue, had this power. Recent experiments, however, indicate that under certain highly elaborated conditions they, too, can be made to live and even grow indefinitely and that this growth can not only be observed but measured under the microscope. Many attempts had been made by many individuals to grow tissues artificially to see their development, their functions, and decay, in both health and disease. This can now be done by taking pieces of living tissue from the body, for science has never produced a single living cell, and placing it in artificial media made out of blood plasma especially prepared, for nutrition for such a bit of tissue deprived of access to the normal circulation of the blood is the prime condition for such growth.[179] Indeed, until Carrel, who had long been interested in the regenerative processes of scars, succeeded in actually causing cells of the connective tissue to grow after being deprived of the circulation of the blood, this was supposed to be impossible. Leo Loeb had already produced artificial growth within and without the body as early as 1907, and in such processes that utilized the body fluid it was found that the same course was followed as in nature, so that the processes in such culture media approximated those that followed grafting. In 1907 Harrison gave details of such a process that seemed convincing, although he worked only on cold-blooded animals, cultivating nerve fibers from the central system of the frog. Carrel extended this method to warm-blooded creatures and mammals, studying especially the laws of regeneration of tissues after surgical wounds.