AGING, the Biological Problem of. - The problem of the senescence of organisms is linked to the condition of the life cycle (v. BIOLOGICAL CYCLES). Every species has its own cycle of development: it grows, reproduces and then, after a period of senescence, dies. There is also a relationship between senescence and growth, in the sense that, as long as there are manifestations of growth, there is no senescence.
A problem of natural interest, and one that serves to clarify the concept of senescence, is the one posed by protozoa. These animals, according to Weissmann's concept, would be immortal, in the sense that (naturally from a theoretical point of view) they never age and never die because through reproduction they save themselves from this fatal destiny of all living beings. In fact, a protozoon, at a given moment, and still in the fullness of its vitality, divides and gives rise to two organisms, themselves also young like the parent. Thus two new organisms have been formed, without the first having aged or died. If one cannot speak of senile phenomena in these unicellular organisms, nevertheless the phenomenon of death can be observed in the sense that, after a certain number of generations, nothing more remains of the matter that constituted the body of the initial parent. In multicellular animals, on the other hand, a life cycle becomes established that culminates in death. In general, death is preceded by a period of senescence.
Attempts have been made to explain the phenomenon of senescence by a process of dehydration that the organism undergoes from its earliest age, indeed, to be more exact, even before birth, during embryonic and fetal development. Consider that, whereas in a human embryo 97% of its body weight is due to water (almost entirely water), at 8 months of intrauterine life water is present at 83%, in the newborn at 70%, it can reach 65% in the adult and almost 58% in the old person. The phenomenon of colloidal "hysteresis" has also been considered as a factor of senescence: this word indicates the growing difficulty of a hydrophilic colloid in passing from a condition of gel to that of sol and vice versa, that is, the growing difficulty of reversibility. And since it has been demonstrated that in the living cell there is a continuous reversibility, and on the other hand that all colloids are subject to this law of aging, it is easy to understand how this phenomenon has been applied to explain aging in the biological sense. Other factors invoked are that of gradual mineralization and that of the gradual accumulation of catabolites in relation to a growing difficulty of permeability of the cell membrane to the passage of these products, which are thus retained within the cells themselves.
If certainly these facts can be recognized during the phenomena of senescence, one must not however attribute to them the value of causal factors. The true and only factor is another, and all the phenomena considered thus far are nothing but consequences. The true factor is cellular differentiation: this is a notable privilege of multicellular animals, which permits the highest functions, but which condemns the organism to a limited cycle of life. The cells of metazoa associated in the higher organization, by the principle of the division of labor, differentiate themselves by assuming the structures most suited to the various functions, for which they specialize. But with this cellular specialization the cell loses the possibility of dividing and reproducing, and this leads to the senescence of the cell, during which the phenomena just described of dehydration, colloidal hysteresis, mineralization, etc., take place and fatally lead to death.
That this is the true cause of senescence and death is demonstrated by many experiments: if one makes a culture of cells from a higher organism, as Carrel did with cells from the heart of a chicken embryo, and one prevents, by means of embryonic juices, these cells from differentiating, they multiply theoretically indefinitely: a strain was cultivated for over 26 years, that is, for a period well longer than the normal life cycle of the chicken. Thus it is also explained how, through their multiplicative activity, conditions of senescence do not occur for the cells of the germinal line, and theoretically all of them could give rise to new organisms; this condition induced Weissmann to extend his principle of immortality also to the cells of the germinal line of metazoa.
Studying the life cycle of an animal and the cycle of cells, one observes that only for a few tissues is there a coincidence of cycles. Among these are nervous tissue and striated muscle tissue. In these tissues the cells lose the faculty of multiplying from the first days of embryonic life and differentiate and accompany the individual throughout life. These are the tissues that Bizzozero defined as having "perennial elements." In the cells of these tissues one observes senile phenomena that coincide with the senility of the organism. But in very many other tissues the life cycle of the cells is quite short, and many are produced, differentiate, age and die within the brief span of a few weeks. These are the tissues with "labile elements" of Bizzozero, those in which functional wear necessarily leads to a brief life cycle. As an example, one cites the cells of our epidermis, which continuously die and, after having formed the horny layer, desquamate and are eliminated from the organism. This continuous "death" of our tissues is possible insofar as a zone of the tissue is preserved in which the differentiation of the cells does not occur and in which proliferative activity is conserved. Thus even these cells of "cambial" tissues, to use the botanists' term, which always actively multiply, never age, just as the cells of the germinal line do not age. It is the multiplicative activity, which continuously renews them, that prevents the manifestation of the fatal process of senescence. Thus the germinative layer of the skin of an octogenarian has the same structure and the same youthfulness as that of a newborn.
One must therefore, in order to study the phenomena of cellular senescence, refer above all to the perennial cells, that is, those that accompany the individual throughout the entire life cycle. For example, interesting is the picture of senescence of nervous cells: the cell shape is modified, special processes, the paraphytes, are produced, cavities, known as "fenestrations," are formed, granules of melanic pigment and droplets of fat accumulate. The accumulation of pigment and of fat are two of the most conspicuous and common manifestations of the senescence of cells.
If one considers the organism as a whole, one finds that, more than the general phenomena just recalled, secondary factors intervene in senescence which in the end become the principal cause of the phenomenon. In this connection one recalls arteriosclerosis, that is, the loss of elasticity of the arteries, and the alterations of the peripheral capillary network. Especially important is the latter alteration, which is the cause of a slowing of the blood circulation. If to this fact one adds the gradual decrease in the permeability of the cell membrane, one understands how the catabolites are more difficult to remove from the cells and how the nutrient more difficultly reaches them. It is precisely the accumulation of catabolic products, which act as toxic substances, and the deficiency of nutritive substances that provoke the phenomena of cellular atrophy and of sclerosis.
