Jayant Radhakrishnan
Chicago, Illinois, United States

Important and affluent people have always sought immortality, or at least an inordinately long life, and medical systems have tried to deliver. Āyŭrvēdic, Egyptian, Chinese, Persian, and Greco-Arabic (Ǖnāni) medical systems prescribe diet, exercise, rest, mental peace, and herbs for longevity by promoting healthy living. Āyŭrvēdă also advocates Răsăyānă, an intense system that is believed to rejuvenate the body at the cellular level. The basic idea is to maintain equilibrium amongst bodily functions and also between the body and the environment.

In 1850, Claude Bernard described a totally different concept for the internal environment (milieu intérieur) of the body, stating, “The constancy of the environment presupposes a perfection of the organism such that external variations are at every instance compensated and brought into balance.”¹ Charles-Édouard Brown-Séquard went further and proposed that the body secreted substances (now known as hormones) that pass directly into the blood to modulate the internal environment. To prove his point, he injected himself subcutaneously on ten occasions with “a liquid containing a small quantity of water mixed with the three following parts: first, blood of the testicular veins; secondly, semen; and thirdly, juice extracted from a testicle, crushed immediately after it has been taken from a dog or a guinea pig.” He claimed that at seventy-two years of age he was rejuvenated, his intellectual capacity had returned to previous levels, he was now as strong as he had been many years ago and upon testing with a dynamometer his limbs were considerably stronger, the length of the jet of his urinary stream was four times longer, and he “had a greater improvement with regard to the expulsion of fecal matters than in any other function.” He believed that the effects of the injections lasted for about five and a half weeks. He also mentioned that a Dr. Variot injected three other older men with the concoction, and they also improved.² The solution did not improve his longevity, however, for he died five years later.

Greenblatt calculated that to obtain a therapeutic dose of testosterone would require about a quarter ton of bulls’ testicles³ and a recent study employing Brown-Séquard’s method produced testosterone concentrations that were four orders of magnitude below that required to produce a biologic effect.⁴ Another striking example of the placebo effect was Leo Stanley’s early twentieth-century study at San Quentin State Prison, where he administered 1,000 injections of animal testicular matter to 656 people. The subjects reported remarkable improvements in weakness, senility, mental health, epilepsy, rheumatism, acne, neurasthenia, vision, asthma, sex drive, impotence, and constipation. Only tuberculosis did not respond.⁵ Brown-Séquard’s report unleashed a period of “organotherapy” by questionable practitioners who used preparations with dubious, varied constituents.

The next era of organotherapy originated with Serge Abrahamovitch Voronoff who announced in 1919 that a man would be rejuvenated if an ape’s testis was transplanted into him. George Frank Lydston, the professor of genito-urinary surgery and venereal diseases at the University of Illinois, immediately announced that he had “done everything that Voronoff had done, and had done it better and earlier.” When Dr. Max Thorek asked Lydston about it, he was invited to Lydston’s office, where Lydston stripped and told Thorek to take a look. He had three testicles, the extra one being from a healthy young man who had been executed.⁶ Indeed, he had first published his papers on the subject in 1914.^7,8 After hearing Voronoff speak and demonstrate his technique in Chicago, Thorek experimented with testicular transplantation. He concluded that if the testis in situ had any function, a transplant could reactivate it for a time, but he was not enthusiastic about the procedure.^9,10 Voronoff’s wife translated his works from French into English, rendering testicular transplantation the latest fad for rich older men.

On June 12, 1922, the wealthiest man in Chicago, Harold Fowler McCormick (no relative of Colonel Robert McCormick of Chicago Tribune fame), took over the entire sixth floor of Wesley Memorial Hospital with guards at all the doors. His attending physician was Dr. Victor Darwin Lespinasse. The Chicago press was electrified because Dr. Lespinasse was a noted testis transplanter, and McCormick was involved with a couple of young opera singers since divorcing his wife. After carrying out a $50,000 operation, the doctor stated, “The story that any part of any other human body has been or will be used in the treatment of Mr. McCormick has not the slightest foundation in fact.” The reporters then decided that he must have received monkey testicles. Two months later, McCormick married Ganna Walska. After McCormick died, she wrote in her autobiography that she had hoped she and her husband could share a “divine companionship of the spiritual love,” but after his surgery McCormick became “insatiable in his search for the realization of the physical.”¹¹ The craze for testicle transplants became so widespread that men were kidnapped from the streets and knocked out only to wake up with empty scrotal sacs. An Illinois state legislator even tried to make involuntary castration a death penalty offense.¹²

An Austrian physiologist, Eugen Steinach, claimed he “cured” homosexuality by removing a homosexual’s testes and implanting the glands of a heterosexual male in him. This belief led to a series of castrations and gonadal transplants.¹³ Steinach had previously demonstrated that testicular interstitial cells secreted an unnamed masculinizing substance, so he named them “puberty glands.” He hypothesized that spermastasis (blocking semen flow) would stimulate interstitial cells to produce more of the substance. He initially divided the efferent ducts between the head of the epididymis and the upper pole of the testis. Later, he simplified the procedure by ligating the vas deferens close to the epididymis but only on one side, to avoid sterilizing the patient. He reported that his procedure either improved or cured asthenia, neurasthenia, hearing and vision loss, baldness, obesity, hypertension, and impotence. Tuberculosis was again resistant to treatment.^14,15

Thorek was intrigued by the vasal ligation procedure after reviewing Steinach’s experiments on rat rejuvenation. After squandering much money and time experimenting with the procedure, he published an article stating that the operation had limitations.^16,17 Upon reading Thorek’s report, Steinach ghosted him, in today’s parlance.¹⁸ Both procedures lost their popularity by the end of the 1920s, partly because they did not work, but also due to a dearth of disposable income with the onset of the recession. A few years later, testosterone (T) and other androgens were isolated from biological sources and then synthesized.¹⁹ Illicit use of T and other androgens by professional and amateur athletes acting as individuals or as members of teams from certain countries is well known. After ninety years of usage, the only true medical indication for T is as replacement therapy for pathological hypogonadism. Testosterone and other androgens are often used for made-up diseases and for other indications than their intended ones. The drugs have not resulted in longevity or rejuvenation, and their side effects have caused serious problems.²⁰

The strategies described above only attempted to address male rejuvenation. In females, it was impossible to block only the reproductive part while leaving the interstitial cells unaffected, either surgically or by radiation. Voronoff chauvinistically dismissed female rejuvenation by declaring that, since women live longer than men, they could wait a while before a remedy to intensify and prolong their lives was developed.²¹ Alexander Bogdanov was the first to try a rejuvenating technique applicable to both sexes, although it was based upon convoluted thinking. He decided that blood exchange therapy would stimulate the human body because some unicellular organisms benefit by fusing and exchanging protoplasm. The first eleven exchanges he received were uneventful. Following the twelfth transfusion, he died of a hemolytic reaction even though the blood groups were identical and the crossmatch was compatible. It is unclear whether he had developed antibodies to an antigen in the donor’s blood due to prior transfusions or if the reaction occurred because the donor had tuberculosis and malaria.²²

Bogdanov’s studies remained hidden in the secretive USSR. However, during the Cold War, both the US and USSR experimented with methods to increase the oxygen-carrying capacity of blood in astronauts/cosmonauts, fighter pilots, and Special Forces. Athletes looking for an edge learned about these and began using autologous and homologous blood transfusions; perfluorocarbons or hemoglobin-based oxygen carriers; erythropoietin (to boost red cell production); hypoxia-inducible factor stabilizers (to activate erythropoietin); and myo-inositol trispyrophosphate (to shift the oxygen dissociation curve to the right). Hazards caused by hyperviscosity of the blood such as strokes, pulmonary embolism, myocardial infarction, or even the risk of infection being transmitted from the donor were ignored. Blood doping was banned by athletic organizations in 1986. The latest iteration of blood product use for rejuvenation is “young plasma therapy.”²³ One method is to exchange an older person’s plasma for plasma from a young donor, or to use albumin or intravenous immunoglobulin. The other technique is a direct transfusion of fresh-frozen plasma or plasma fractions derived from a young donor. Limited literature to date demonstrates elevation in surrogate endpoints such as biological markers but no clinical reversal of aging.

The latest possible magic potion for rejuvenation appears to be stem cells. The term stammzelle (stem cell) originated as far back as 1868 as a term for the original unicellular organism that gave rise to all multicellular organisms,²⁴ but stem cell function was first demonstrated in 1963.²⁵ The next great advances occurred in 2005 and 2007, when Shinya Yamanaka reprogrammed skin cells into induced pluripotent stem cells (iPS).²⁶ They have been tried as a treatment for various diseases and have also been promoted for many pseudo-scientific uses. Legitimate, scientific attempts at rejuvenation consist of selectively killing senescent cells with senolytics followed by use of the so-called Yamanaka factors to turn adult cells into iPS for epigenetic reprogramming. One remarkable result has been the rewinding of the biological clock in skin by approximately thirty years.²⁷ Other researchers who restored vision using such reprogramming in mice²⁸ now have US Food and Drug Administration approval for a Phase-1 trial of partial epigenetic reprogramming for open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy.²⁹ Three Yamanaka factors will be delivered by modified adeno-associated viruses to the retina in one eye. Oral doxycycline administration will be the genetic switch controlling protein expression.³⁰ An important concern is that partial reprogramming has caused cancer in laboratory animals, and human safety has not yet been studied. The injected proteins could also cause an immune reaction.

The previous techniques were all based upon what was considered reliable evidence at that time, just as is the case with reprogramming today.²¹ Only time will tell whether this is a scientific answer to the quest for the mythical “Fountain of Youth.”

References

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