Extending the Maximum Life Span:
Joseph Knoll, M.D., is a Hungarian neurochemist and pharmacologist. He is probably best known for developing the drug deprenyl (also known as Selegiline), the first selective MAO-B inhibitor, and he has researched the properties of deprenyl for over half a century.
MAO is Monoa-mine Oxidase, an enzyme in the brain that breaks down neurotransmitters. By inhibiting the production of MAO, you increase the longevity of neurotransmitters in the synapses between neurons, and, consequently, the effects of those neurotransmitters. MAO-B is specific to break down the excitatory neurotransmitter dopamine. So by inhibiting MAO-B, you enhance the effects of dopamine in the brain.
Dr. Knoll is also the author of the book The Brain and Its Self: A Neurochemical Concept of Innate and Acquired Drives (Springer, 2005), which summarizes his life's research and his fascinating speculations about the relationship between brain activity and culture.
In this book, Dr. Knoll describes how his experience as a Nazi concentration camp survivor helped to inspire and motivate much of his scientific research. Although his parents were sent to the gas chamber when he was a teenager, Dr. Knoll survived because he spoke fluent German and was chosen to serve as the personal servant to the Chief of the SS guards. In 1945, after the war, Dr. Knoll returned to his native city of Budapest. He earned his M.D. from the University of Budapest in 1951, and later became a professor and the head of the Department of Pharmacology at the Semmelweiss University of Medicine in Budapest.
In the early 1950s, Dr. Knoll helped to pioneer research into the physiological basis of innate and acquired drives in animals. Trying to make sense of his experience in the Nazi concentration camp, he became interested in how animals acquire new drives. The research that resulted from his interest in this subject centered around studying the brain changes in rats that had been trained to have an acquired drive for an unnatural object—a glass cylinder.
This acquired drive—which urged the animals to search for, and jump to, the rim of a thirty centimeter-high glass-cylinder, and then crawl inside—would often override the animals' instinctive drives for food and sex.
Dr. Knoll first synthesized deprenyl in his Budapest laboratory in 1961 and showed that deprenyl improves the availability of dopamine, and slows its age-related decline by acting as a selective MAO-B inhibitor. As well, it has an enhancer effect, and it helps maintain healthy brain cells, particularly in the dopamine-producing area of the brain known as the substantia nigra—the area of the brain that degenerates with Parkinson's Disease. For this reason deprenyl has been used as an effective treatment for Parkinson's Disease. It has also been shown to be an effective treatment for Alzheimer's Disease and other brain disorders that result in cognitive decline.
Deprenyl has been shown to have many uses as a cognitive enhancer. It is a moderate-level stimulant and antidepressant that has been shown to improve memory, protect the brain against cell damage, alleviate depression, extend the life span of laboratory animals, and heighten sexual desire in both men and women. This impressive substance is available by prescription in the U.S., and although it is primarily prescribed to help people with Parkinson's disease, memory disorder problems, and sometimes depression, a lot of healthy people also use deprenyl to improve their mental performance. In fact, Dr. Knoll himself takes deprenyl every day, and recommends that every sexually mature person should be doing the same.
Along with other cognitive enhancers, such as hydergine and piracetam, I think that deprenyl has incredible potential for enhancing memory, accelerating intelligence, and improving concentration. There is a good deal of scientific evidence to support these claims. Find a summary of the scientific studies in this area in John Morgenthaler and Ward Dean's book Smart Drugs and Nutrients II.
Many people report that deprenyl and other "smart drugs" have sexually-enhancing "side-effects," although deprenyl appears to have the leading reputation in this area. According to Dr. Dean—the coauthor of Smart Drugs and Nutrients—"anything that improves brain function is probably going to improve sexual functioning." This is probably because sexuality and health go hand-in-hand, and sexual vitality is a pretty good indicator of overall health.
Dr. Knoll and colleagues first reported indications for deprenyl's potential as a sexuality enhancer in 1983, with reports that old male rats had increased their "mounting frequency" and "intromission" when they were treated with deprenyl. This contrasted dramatically with the untreated control animals. Many anecdotal reports, from both men and women, have confirmed that these aphrodisiac-like effects apply to humans as well. Because deprenyl inhibits MAO—the dopamine-destroying enzyme—levels of the excitatory neurotransmitter dopamine rise in the brain, which generally causes people to feel more pleasure and become more physiologically aroused.
Interestingly, unlike most other MAO inhibitor drugs (such as the antidepressant Nardil), there are usually no dietary restrictions necessary when one takes deprenyl. When taken at moderate levels (under 10 mg), deprenyl only inhibits the action of a specific type of MAO—MAO B—which doesn't interfere with the body's ability to metabolize the dietary amine tyramine, like a broad-spectrum MAO inhibitor does. This is why most other MAO-inhibiting drugs carry the serious danger of triggering a hypertensive reaction if one eats tyramine-rich foods, like cheese or wine. Deprenyl has been described by researchers as working with great precision in this regard, and the physicians that I spoke with agreed that it was unusually safe.
In fact, deprenyl is better than safe. This truly remarkable drug has also been shown to increase the maximum lifespan of laboratory animals by close to forty percent. This is the equivalent of a human being living to be around one hundred fifty years of age. Giving deprenyl to animals is the only experimental treatment—besides caloric restriction—that has been shown to increase maximum life span.
To fully appreciate how significant deprenyl's life extension potential is, one has to understand the difference between maximum life span and average life span. Many factors can affect the average lifespan (or the "normal life expectancy") that an animal lives—genetics, diet, exercise, nutritional supplements, mental attitude, etc. However, even under the very best of conditions, there is an upper limit at which the longest-lived animals of a particular species can survive, and that is the animal's maximum life span.
The average life span of a human being is approximately seventy to eighty years. However, the maximum life span of a human being is around one hundred twenty years. The laboratory animals in the deprenyl studies showed a forty percent increase in maximum life span, the human equivalent of living one hundred fifty years. Since deprenyl's primary effects work the same in all mammalian brains, it stands to reason that deprenyl's life extension effects are likely to carry over to humans, just as the mental benefits do. Many people have certainly verified that the increase in sex drive occurs in both humans and laboratory animals.
How people can utilize deprenyl for its cognitive enhancing and anti-aging benefits, and what type of anti-aging treatments might be available in the future.
As a survivor of Auschwitz, and one of the 1,300 survivors of the "Dachau Death Train," I had the opportunity to directly experience a few typical representatives of this type of manipulated human beings, and had more than enough time and direct experience to reflect upon the essential changes in the physiological manipulability of the human brain. It was therefore not just by mere chance that, when in the early 1950s I finally had the opportunity to approach this problem experimentally, I decided to develop a rat model to follow the changes in the brain in the course of the acquisition of a drive from the start of training until its manifestation.
Successful clinical studies with deprenyl were executed in depression and in the two age-related neurodegenerative diseases: Parkinson's Disease and Alzheimer's Disease. The first clinical study performed in depressed patients by Dr. Varga with deprenyl was published in 1965. The clinical use of deprenyl in Parkinson's Disease started in 1977. The first two papers demonstrating the effectiveness of deprenyl in Alzheimer's Disease appeared in 1987. Deprenyl was originally developed with the intention to be used as a new spectrum antidepressant. Its effectiveness was first demonstrated with the racemic form of the compound by Dr. Varga and his coworkers in 1965 and 1967, and with the enantiomer in 1971. The first study that corroborated the antidepressant effect of deprenyl was published by Dr. Mann and Dr. Gershon in 1980.
The realization of the peculiar effect of deprenyl—first in Parkinson's Disease and later in Alzheimer's Disease—distracted attention from its antidepressant property which remains unutilized.
Knoll thinks the primary causes of aging in general is survival of the species. Various species live together on earth in a harmonious proportion. This is obviously carefully regulated. One of the seemingly principal regulatory mechanisms that produces equilibrium among living organisms is brain aging. It ultimately leads to the elimination of those individuals who have already fulfilled their duty in nurturing the new generation.
Accordingly, the period from weaning until sexual maturity is reached is the most delightful phase of life, the glorious uphill journey. The individual progressively takes possession, on a mature level, of all abilities crucial for survival and maintenance of the species. It learns to avoid dangerous situations, masters the techniques to obtain its food, develops procreative powers for sexual reproduction and copulates.
This is, at the same time, the climax of developmental longevity. The fully sexually mature individual fulfills its duty. Thus, to maintain the precisely balanced out natural equilibrium among living organisms, the biologically "useless" individual has to be eliminated. According to the inborn program, the postdevelopmental stage of life (aging) begins. The essence of this stage is progressive decay of the efficiency of the catecholaminergic system during the postdevelopmental life span until at some point, in an emergency situation, the integration of the parts in a highly sophisticated entity can no longer be maintained and "natural death," signaled by the disappearance of the EEG signal, sets in.
Regarding the quality and duration of life, the most important aging process is the continuous, slow, age-related decline of the mesencephalic enhancer regulation during the postdevelopment phase of life. This can not be reversed, but its progress can be slowed by the prophylactic administration of a synthetic mesencephalic enhancer substance (for the time being with the daily administration of one milligram of deprenyl). The earlier this protective treatment starts, the better are the prospects to improve the quality of life in the latter decades, which necessarily goes together with an extension of life span.
The average life span in the most developed countries has already exceeded the eighty year level. This change has come about due to the prevention of premature deaths owing to the development of hygiene, immunology, and chemotherapy. The human technical life span (TLSh), close to one hundred twenty years, has remained, however, unchanged.
In Knoll's view, to extend the human life span beyond the TLSh needs the elaboration of an ultimate technique for the prophylactic, daily small-dose administration of a safe synthetic mesencephalic enhancer substance from sexual maturity until death. The attainable upper limit in the extension of the TLSh is obviously unpredictable at present.
Nevertheless, if brain research could, at some time in the future, achieve just a doubling of the TLSh, this will mean for humans the most significant accomplishment that science has ever achieved, since nothing can be more important for the individual than the quality and duration of his/her life.
In the developed countries the proportion of the aged is high, and the estimated number of individuals over sixty-five will increase to 1.1 billion by 2050. Accordingly, the demand on anti-aging therapy is rapidly increasing. This trend explains the already high-sounding proposals for anti-aging treatments.
Since the brain alone ensures that the mammalian organism works as a purposeful, motivated, goal-directed entity, the age-related changes in the central nervous system are of particular importance. And since the enhancer-sensitive neurons in the brain stem work as the engine of the brain, the slow, continuous, postdevelopmental functional decline of the mesencephalic enhancer regulation is of primary importance in the maintenance of the well-balanced equilibrium among living organisms, because it helps to eliminate the individuals who already fulfilled their duty in nurturing the new generation.
For the time being the prestigious task—the maintenance of the mesencephalic enhancer regulation during the postdevelopmental phase of life on the enhanced level characteristic of developmental longevity—cannot be fully accomplished. However, it is already feasible to modestly slow the age-related decay of the catecholaminergic and trace-aminergic tone in the brain via the prophylactic administration of one milligram of deprenyl daily.
The development of BPAP—a synthetic mesencephalic enhancer substance that is at least a hundred times more potent than deprenyl—is by itself a hint that our present knowledge about the mesencephalic enhancer regulation is in a very early stage. Better understanding of mesencephalic enhancer regulation promises to develop more efficient techniques in the future to slow brain aging and prolong human life beyond the TLSh. This physiologically well-founded, feasible, antiaging therapy is likely to remain a method to continuously improve the quality, and prolong the duration of human life.
Humans cannot change natural laws, but by discovering their mechanisms of action they learn to make use of this knowledge. By conquering gravitation man stepped across his naturally given limit and ultimately landed on the moon. By conquering the age-related decline of the mesencephalic enhancer regulation man might in the future step across also this naturally given limit and extend human life span beyond the TLSh.
Dr. Knoll's ambition is to develop a more efficient compound than deprenyl for slowing the age-related decay of the mesencephalic enhancer regulation, and to detect the envisioned unknown mesencephalic enhancer substances, expected to be several thousand times more active than PEA or tryptamine. Currently we are trying to clarify in more detail the pharmacological spectrum of BPAP—our newly developed, tryptamine-derived, synthetic mesencephalic enhancer substance.
