Rejuvenation

REJUVENATION, the restoration of the signs of youth in an aging organism. Rejuvenation represents one of the cherished thoughts of humanity from very distant times. The dream of returning lost youth has been expressed many times in the artistic works of poets (Faust) and has served as the subject of the fruitless quests of alchemists. The concept of rejuvenation has different content when applied to protozoa and multicellular organisms. In the former, the process of reproduction, which reduces to the division of the entire maternal organism into two parts, leaves no "corpse" and thus gives the right to speak of the "potential immortality" of protozoa. The ability for continuous reproduction in cultures of protozoa is maintained by the process of conjugation that occurs from time to time. This process reduces to the exchange of a part of the small nucleus (micronucleus) between two individuals and to the reorganization of the large nucleus (macronucleus). Initially, the assumption was made that the process of conjugation, and in particular mutual fertilization by parts of the micronucleus, has the significance of rejuvenation, as a result of which the ability for vegetative reproduction, which periodically fades in cultures, is restored. However, subsequently, Woodruff, Metalnikov, Doflein, and Calkins showed that continuous vegetative reproduction in paramecia can also be carried out in the absence of conjugation (by isolating the divided individuals) for more than 10,000 generations. In such infusoria, however, a process of reorganization of the macronucleus occurs from time to time, following which the weakened rhythm of reproduction is strengthened again. Thus, it is not the exchange of micronucleus substance that has rejuvenating significance, but rather the reconstructive phenomena in the macronucleus. The possibility of rejuvenation in protozoa, associated with the absence of a pronounced separation of the somatic part of the organism from the generative, has no exact analogy in multicellular organisms. The differentiation of the organism into soma and germ cells leads to the fact that the somatic part undergoes aging and dies during individual development. Attempts to achieve rejuvenation of the somatic part of the organism can be based on the regenerative capacity of many tissues. Until now, however, the question remains unresolved as to whether the process of regeneration testifies to the reversibility of developmental phenomena or whether it proceeds at the expense of reserve materials that have preserved in the adult organism the pluripotency characteristic of young tissues. The individual development of multicellular organisms passes through a series of stages, ending in old age and death. The phenomena associated with aging are extremely diverse and concern essentially all parts of the organism. Morphological and functional changes in the nervous system, cardiovascular system, bones, active mesenchyme, and endocrine glands have been investigated and described in extreme detail. Attempts have been made to reduce senile changes in the protoplasm of all somatic cells of the organism to colloid-chemical processes (hysteresis of protoplasm, Ruzicka). It is undoubted, however, that these processes do not exhaust the essence of aging, just as it is not exhausted by indications of pigment accumulation in nerve cells (Harms), the disappearance of pigment in hair, degenerative changes in the sex glands, etc. Some researchers are inclined to attribute a decisive role to senile changes in the endocrine glands (Bouin, Ancel, Steinach, Zavadovsky, and others). The source of this view is the experiments of Brown-Séquard (1889), performed on himself and consisting of injecting extracts from the male sex glands of animals with a distinct rejuvenating effect. In 1914, Harms, and in 1920, Steinach, published the results of their experiments on guinea pigs and rats. The former transplanted the sex glands of young animals to old ones, and the latter performed an operation of ligating the vas deferens. The result of such ligation was the partial death of the generative elements of the testis and the proliferation of Leydig and interstitial cells (see Interstitial gland). The general condition of the operated animals, as a rule, improved; lost hair was replaced by new, appetite, pugnacity, libido, and potentia generandi were restored. Many researchers who repeated Steinach's experiments on various animals and on humans came to similar conclusions, although in a number of cases the rejuvenating effect was less distinct, less complete, and sometimes absent altogether. Harms's experiments with the transplantation of sex glands from young animals to old ones were widely repeated by Voronoff on goats, rams, and humans. In the latter case, Voronoff practiced the transplantation of glands from monkeys, in a number of cases with great success. In the light of these experiments, a completely incorrect idea may be created about the mechanism of senile changes and the possibilities of rejuvenation. The first reaction to the one-sided fascination with the idea of rejuvenation through the revitalization of the incretory activity of the sex glands was the view that the key to the problem of old age and rejuvenation does not lie in the sex glands alone. Mechanistically thinking biologists, in search of the "causes" of developmental phenomena lying outside the aging tissues and organs themselves and concentrated in certain parts of the organism (endocrine glands), turned to the hormones of other incretory glands. Thus, Pende points to the beneficial effect of the simultaneous transplantation of sex glands, the thyroid gland, and the pituitary gland. A similar idea is developed by M. Zavadovsky (1931): "In order to return an aged organism to a young state, it is necessary to create for its tissues the conditions of existence that characterize young age, and first of all to return to it a young incretory polyglandular network. Since a young organism differs from an old one not only in the state of the sex gland but also in the state of other incretory glands, then, proceeding from this, we have been advocating since 1923 the necessity of transplanting to an old organism not one sex gland, but a network of incretory glands of a young individual." The practical effect of rejuvenation through operations leading to the renewal of endocrine glands should not create confidence that in this way one can arrive at the establishment of the true essence of senile changes in the organism. Hormones of the endocrine glands can exert a sufficiently deep influence on the organism of vertebrate animals and humans; a similar effect can also be exerted by the transplantation of other organs (e.g., the liver in Romeis's experiments); a beneficial effect can also be expected from a certain diet, as well as from the introduction of lactic acid fermentation products into the intestine (Metchnikoff). In short, there are many conditions, the presence of which is necessary for maintaining the tone of the organism. This means that neither one of these conditions individually (e.g., the sex gland) nor a complex of these conditions (the totality of endocrine glands) can be considered as determining this or that state of the development of the organism. At the same time, one cannot deny the fact that the activity of the incretory glands, and the sex gland in particular, plays an essential role in maintaining a number of signs characterizing a young organism and that the renewal of the sex gland leads to changes that may bear the name of rejuvenation. The practical results achieved in this direction, however, do not give grounds to assert that the essence of senile changes reduces to a disturbance of the endocrine functions of the organism. The organism is a totality, and its basic properties, in particular the regularity of individual development, are determined by this totality, i.e., by the interaction of all interconnected parts and the relationship of the organism with the environment. Only penetration into the essence of the process of development of the organism and the uncovering of the laws of this development will lead to the construction of a Marxist theory of old age and will provide a methodological basis for experimental attempts at rejuvenation. The source of senile changes in the organism as a whole must be sought in the historical course of the individual development of the organism and thus in the organism itself as a unity. Senile changes in individual parts of the organism can be understood only by studying the development of these parts themselves and their interaction with all other parts of the organism as a whole.

Blyakher. When the idea of rejuvenation received a physiological experimental basis, it found fertile ground among clinicians. The ideas of E. Steinach could not remain within the narrow walls of laboratories; they had to find the widest application in life, in human pathology. Ligation of the vas deferens as an auxiliary surgical operation was performed even before Steinach and was proposed by Mears in 1896 for the treatment of hypertrophy of the prostate gland. In the same year, Helferich and Lennander proposed resection of the vas deferens for the treatment of hypertrophy of the prostate gland, and Isnardi proposed cutting and ligation of the stump of the vas deferens for the same purpose. The proponents of these operations themselves saw that success from the operations was not always obtained and began to explain the failures by incorrect selection of cases, namely: only cases of hypertrophy of the prostate gland not accompanied by distension of the urinary bladder and its infection are indicated for the operation. According to the statistics of Burckhardt, out of 323 cases of ligation of the vas deferens, success was obtained in only 25%. Now, when Steinach attributes a rejuvenating effect to this operation, we cannot help but be puzzled by the question: why did none of the authors who observed successful results from the use of ligation of the vas deferens for hypertrophy of the prostate gland simultaneously note its "rejuvenating" effect? Undoubtedly, only its excellent effect on the general condition of patients was noted, but the beneficial effect of any palliative operation for hypertrophy of the prostate gland can be fully explained by the elimination of a number of clinical symptoms that disturb the patient's sleep (frequent urges to urinate at night), intoxication by retained (residual) urine, etc. Almost simultaneously with the proposal to use ligation or resection of the vas deferens for the treatment of hypertrophy of the prostate gland, this same operation unexpectedly found application for a completely different reason. In the USA, in the state of Indiana, there exists a law by virtue of which habitual criminals, idiots, the feeble-minded, and rapists are subject to sterilization. In accordance with this law, Sharp began performing the operation of cutting the vas deferens in 1899, and over a period of more than 20 years, he produced 236 observations on the results of this operation. Not once were any adverse symptoms noted; on the contrary, "in all cases," writes Sharp, "after several months, the operated patients invariably expressed to me verbally or in writing the most heartfelt gratitude regarding the consequences of the operation performed on them. They claimed that this operation relieves all kinds of nervous suffering, strengthens sleep, and increases physical energy. My acquaintance with the physiology of the reproductive system allows me to clearly understand that all these phenomena are nothing other than the natural consequences of the operations we perform." This is how Sharp spoke about the role of vasectomy long before Steinach proposed it as an operation for rejuvenation. Regarding the technique of performing the Steinach operation, initially Steinach himself used ligation of the efferent ducts (vas deferens), but in view of the difficulty of avoiding injury to the delicate vessels passing along the duct, he found that the most suitable place for applying a ligature is the space between the testicle and the head of the epididymis. Here the coni vasculosi pass, completely without coming into contact with the vessels. This method has the further advantage that, thanks to the proximity of the ligation site to the testicle, the effect of the ligation itself manifests earlier, and the "puberty gland begins to grow rapidly and exert its effect." The first Steinach operations on humans, performed by Lichtenstern, were accompanied by exceptional success: in a case of premature aging (senium praecox) at 44 years of age, accompanied by exhaustion and inability to perform physical work, absence of libido for several years, and almost complete disappearance of potentia, after 4-5 months there occurred a complete restoration of physical strength, libido returned, and potentia began to manifest very vigorously, as in the days of youth (coitus 3-4 times a week). "After 1 1/2 years, this man, with a fresh face, without wrinkles, and with a vigorous figure, gives the impression of a completely healthy young man" (Steinach). At the present time, there is a sufficient number of reports in the literature in which both the personal experience of individual authors and collective statistics have found reflection. Thus, Lichtenstern published 26 cases of the Steinach operation, Schmidt (P. Schmidt) - 24, Sand (K. Sand) - 18, Benjamin - 114 cases; in Russian literature, summary statistics yielded 193 cases (Gorash). The comparatively large material of Benjamin, who obtained very good results in the sense of rejuvenation in 77% of cases, deserves attention. The effect of bilateral ligation occurs faster and more noticeably than from unilateral, and on average appears 6 weeks after the operation. The duration of the operation's effect has not been traced, and there are only indications that it is not short-lived but lasts for a considerable time. What indications have been developed by clinicians for the Steinach operation? In the first place, of course, is premature aging with a decrease in metabolism and work capacity, with a decline in energy, sexual function, etc. In the second place, one should place physiological old age, in which we have the right to expect a positive effect from the Steinach operation. Despite the fact that Steinach proposed ligation of the vas deferens exclusively for the purposes of rejuvenation, this operation has also found wider application. It began to be used in various severe diseases or cachexias as a preliminary intervention stimulating the organism; in endocrine disorders associated with a decrease in the function of the sex glands; in some forms of impotence; in depressive states, etc. From this enumeration of indications for the Steinach operation, it is evident that in the view of clinicians, it has lost its specific purpose and has taken on the character of a stimulating, or, more precisely, endocrine-stimulating operation (Gorash). If the operation is performed for premature aging (senium praecox) and at the same time the preservation of the ability to fertilize (potentia generandi) is pursued, then the operation should be performed only on one side. The rejuvenation operation is contraindicated, or rather useless, in cases of profound decrepitude, significant lesions of the sex glands, etc. The views of authors diverge on the question of indications for the Steinach operation in eunuchoidism; thus, Benjamin considers it indicated in eunuchoidism, whereas Gorash considers it useless in this case. When establishing indications for the Steinach operation, it is necessary to strictly separate the phenomena of old age (aging) from diseases of old age; for the latter, the Steinach operation is not indicated. Some authors attribute not only favorable consequences to the Steinach operation, but also harmful ones. Mendel describes a case of a 61-year-old old man in whom a severe mental disorder developed after the operation, leading to the patient's death 3 months later. However, Bonhoeffer disputes Mendel's case and considers the psychosis that developed in the patient to be arteriosclerotic. Payr, in connection with this, cites his own 3 cases in which severe psychosis appeared after vasectomy. He also draws attention to the place in the monograph by Socin and Burckhardt on hypertrophy of the prostate gland, where it is stated that after vasectomy, one could very often observe an unusually rapid aging. All these remarks stand in complete contradiction to the rest of the mass of observations on the Steinach operation. In the literature, there are indications of the necessity of dosing the Steinach operation, for which one should perform ligation of the vas deferens in one session only on one side or limit oneself generally to unilateral ligation (Lichtenstern, P. Schmidt), but the indications for this dosage have not yet been developed. Undoubtedly, the very question of the dosage of the operation was put forward in connection with the unpleasant consequences noted in the literature, caused by simultaneous ligation of the vas deferens on both sides. The experience of A. Smirnov in application to the rejuvenation operation leads him to the conclusion that it is necessary to perform a strict selection of material and, at the same time, not to expand, but to narrow the indications for the operation. Smirnov did not have occasion to observe any striking effect of rejuvenation, but the endocrine-stimulating effect of the operation in correctly selected cases is undoubtedly sharply positive. Almost simultaneously with Steinach, Voronoff was engaged in the development of the question of rejuvenation. He, unlike Steinach, attaches greater importance not to the "puberty gland," but to the spermatogenetic epithelium, even if the latter underwent significant morphological changes after transplantation. In testicular transplantation, we have, in Voronoff's opinion, a powerful means for combating the senile state caused by insufficiency or suppression of the internal secretion of the testicles.

Retterer, who conducted histological studies of testicular pieces transplanted according to the Voronoff method over periods ranging from several weeks to 3 1/2 years, traced the evolution that the epithelium of the seminiferous tubules undergoes and arrived at the following conclusions: the epithelium of the seminiferous tubules first turns into reticular tissue, and then into clusters of young connective tissue, arranged in the form of closed follicles or tubules with a narrow lumen, lined inside with concentric rows of flat cells of an epithelial type. Their cytoplasm increases in volume as it moves away from the center of the tubule to the periphery and changes, becoming fibrillar instead of homogeneous and taking on the character of dense connective tissue. With ordinary homoplastic transplantations of testicular plates into various tissues and organs (subcutaneous tissue, muscles, preperitoneal tissue, bone marrow, etc.), a gradual necrosis of the epithelium of the seminiferous tubules and resorption, lasting from 6 weeks to 3 months, is invariably observed (methods of Raug, Lichtenstern, Enderlen, Thorek, and others). In search of the best conditions for performing testicular plate transplantations, Voronoff developed the following technique: the testicle of an anthropoid ape is freed from the epididymis and remains connected to the blood vessels until the very moment of cutting it into 2-4 plates for transplantation; the testicular plates of the ape prepared in this way for transplantation are placed with the pulp onto the scarified surface of the tunica albuginea of the recipient's testicle and are sewn on with four catgut sutures. After this, the membranes of the testicle are sutured tightly. Voronoff considers the most minimal duration of the transplant's stay outside the organism—no more than one to two minutes—to be a condition for the successful engraftment of the transplanted pieces; furthermore, no more than two transplants are transplanted onto the tunica albuginea of a human testicle at the same time. Voronoff and Alexandrescu provide data on 475 operations; the duration of observation was from 3 to 6 years. If one takes only testicular transplantations performed for the purpose of Rejuvenation, they are divided into 2 groups of cases, namely: premature old age (from 55 to 70 years) and old age (from 70 to 85 years). The first group, comprising 236 people, included people in whom a decrease in physical strength and capacity for mental work, as well as a weakening of sexual functions, was noted; in this group, success was achieved in 90%. The second group, comprising 64 people, included people in whom general weakness, decrepitude characteristic of this age, and sexual impotence were noted; success was obtained in 74%. During the first few days after testicular transplantation, strong psychological and sexual excitement is observed, which soon fades, and "the operated patients do not experience any, or at least any obvious, beneficial effect of the transplantation for one to two and even three months" (Voronoff); only after 2-3 months is a very noticeable improvement in their psychological state obtained: improvement in memory, increased capacity for mental work, restoration of sexual functions, etc. In the case of successful transplantations, the result holds steadily for 4-5 years. At the end of the 5th or 6th year, all morphological and physiological phenomena associated with the transplantation disappear. All these phenomena associated with the transplantation of testicular plates, Voronoff and Retterer explain not only by the action of the hormones of the transplanted plates but also by their stimulating effect on the remaining cells of the testicles of the operated subject. As for the material for testicular transplantation in humans, the transplantations from anthropoid apes proposed by Voronoff are far from feasible everywhere for a number of reasons. In view of this, articles have appeared proposing to transplant plates of a testicle removed during tuberculosis of the testicles and their appendages (Payr), or plates of a testicle from a cadaver. If one approaches the evaluation of the results of homoplastic organ transplantations in human pathology, we have the right to expect success, i.e., the engraftment of the transplant, if there is a correspondence of the blood group of the donor and the recipient. In the absence of such correspondence, resorption of the transplants usually occurs (Elansky). Heteroplastic transplantations are doomed to gradual resorption. To which category should the transplantations from anthropoid apes to humans, performed by Voronoff, be assigned? He himself is inclined to assign them rather to the group of homoplastic transplantations: "Such an organ transplantation, performed between such closely related animal species, is very far from heterotransplantation and, on the contrary, very close to homotransplantation; it could be called a homotransplantation, when organs of one animal species, entering the body of another, encounter the same biological conditions" (Voronoff). Unfortunately, Voronoff lacks studies of the blood of the donor and recipient for mutual agglutination. Besides the purposes of Rejuvenation, testicular transplantation is also used for mental diseases. Clinical experiment in this case has outpaced theory, and we can only state that the sex hormone plays a very important role in the treatment of such a severe disease as schizophrenia. The clinic has yet to continue investigating the role and significance of testicular transplantation in schizophrenia.