Originally developed as an immunosuppressant for organ transplant patients, it has found new life as a potential anti-aging drug. Rapamycin has not been approved for this use in humans, but many gerontologists consider it—or similar agents—the best hope for pharmacologically slowing the aging process.
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What is rapamycin
Rapamycin is an immunosuppressant drug prescribed to organ transplant patients. It inhibits the action of one of our proteins - the intracellular protein mTOR.
Rapamycin was isolated in 1972 from a bacterium discovered on Easter Island Rapa Nui - hence the name. For many years it was a little-known drug, but in the early 2000s it was discovered to significantly extend the life of worms, yeast, flies and mice.
In one experiment, researchers gave rapamycin to a group of 20-month-old mice, the equivalent of people of retirement age. They fed the animals small doses for three months, then stopped giving the drug and waited for them to die. Mice usually die around 30 months of age, but the rodents that consumed rapamycin lived an additional 2 months on average. The last survivor died more than two years after the experiment began, at the ripe old age of 3 years and 8 months—equivalent to approximately 140 human years.
Rapamycin has not been tested in this way in humans, but given the similarities between mouse and human biology, scientists suspect it may also extend our lives.
Rapamycin does not prolong, but shortens the life of mice with short telomeres
Rice. 1.
Old (
left
) and young (
right
) mice. They are easy to distinguish by the degree of obesity and the condition of their coat. Photo from nbcnews.com
Rapamycin is one of the most promising candidates for anti-aging pills. Spanish biologists tested how it would act on one of the model objects for studying accelerated aging - mice with short telomeres - and found that it did not prolong their life, as expected, but, on the contrary, shortened it. This is another story about how the causes of aging are closely interrelated, and by acting on one of them, you can inadvertently strengthen the position of the other.
Aging is a set of processes that act on the body simultaneously and gradually bring its death closer. Among them, for example, is the destruction of macromolecules, excessive activation of the immune system, accumulation of incorrectly folded proteins, restructuring of the intercellular substance and many others. It is impossible to single out the main one among them, either speculatively or experimentally. Despite the fact that each research group designates some cause of aging as the key one (otherwise the angle from which the authors look at the problem is unclear), hardly any of the modern gerontologists consider “their” cause to be the only one.
But if there are several reasons, then there must be several ways to deal with them - at least one for each. Moreover, if the causes act together, then anti-aging therapy should be combined in order to cut down each of the roots of the problem. Or will it be possible to find one approach that will affect all causes at once? The latter option is supported by the fact that some causes of aging are still interrelated with each other.
An example is one of the most well-known aging processes, which occurs in most cells of the body - telomere shortening. These are the terminal sections of chromosomes, which consist of “senseless” repeats and perform mainly a mechanical function. They serve as a kind of heel for DNA, which you don’t mind wearing away over time. Before each cell division, DNA doubles, and chromosomes are shortened—some telomeric repeats are lost. Therefore, if nothing is done (and some cells are able to grow the ends of chromosomes back), telomeres gradually wear out. When little remains of them and they are close to disappearing completely, the cell stops dividing. For many cells and the tissues in which they are located, this is a severe loss - if that cell's neighbors die, it will not be able to produce descendants to fill the void.
At the same time, telomeres can shorten for other reasons, unrelated to cell division. One of these reasons may be another culprit of aging - oxidative stress. When mitochondria, for one reason or another, do not cope with their work (for example, there are too few of them, or they do not have enough oxygen), free radicals accumulate in them - chemically active molecules that react with various cellular polymers. They can disrupt the functioning of mitochondria, and if they leak from there into the cell’s cytoplasm, they damage proteins and lipids, which accelerates cell aging. If there are enough of them, then some reach the core. There they oxidize DNA molecules, with the greatest impact on telomeres (see W. Qian et al., 2021. Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction). Under severe oxidative stress, DNA repair systems cannot cope with repairing telomeres and cut off damaged areas from them (see E. Fouqerel et al., 2021. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis). Thus, under the influence of oxidative stress, telomeres become shorter.
If such relationships are established for other causes of aging, then we can imagine a situation where one drug will be enough to stop them all at once. A group of scientists from the Spanish National Cancer Center suggested that rapamycin could be such a drug. This substance is known in medicine as an antibiotic and immunosuppressant, but gerontologists know it as an mTOR blocker. This is a protein complex that stimulates cell growth and development - storage of substances, protein synthesis and active absorption of energy - thereby accelerating cell wear. Rapamycin has repeatedly proven its ability to slow down cell aging and prolong the life of model organisms (see Rapamycin slows down aging in mice, Elements, 02/15/2009), so who knows, maybe it could also solve the problem of telomere shortening?
As a model that suffers seriously from the problem of telomere shortening, the researchers chose mice with a defect in telomerase, the same enzyme that cells can use to grow the ends of chromosomes. In mice, unlike in humans, telomerase operates in many cells throughout life (KR Prowse, CW Greider, 1995. Developmental and tissue-specific regulation of mouse telomerase and telomere length). And despite the fact that mice have telomeres several times longer than ours, in the absence of telomerase they quickly shorten. This becomes especially noticeable in subsequent generations, because descendants inherit shorter and shorter telomeres from their parents. The second generation of such mutant mice lives for about a year instead of the required 2–3 years. The authors of the work suggested that rapamycin could cope with this problem of accelerated aging.
However, the results of the first experiment turned out to be strictly opposite (Fig. 2). The researchers began observing normal and telomerase-deficient mice at 3 months of age. Moreover, within each group, some animals were fed with regular food, while others were supplemented with rapamycin. And if in ordinary mice rapamycin, as in all previous works, shifted the survival curve to the right (that is, it extended life), then in mice lacking telomerase the effect was the opposite: under the influence of rapamycin they began to live less.
Rice. 2.
Survival curves of mice in the experiment.
Dark gray
- control group,
light gray
- wild-type mice treated with rapamycin,
dark green
- mice without telomerase,
light green
- mice without telomerase treated with rapamycin.
The change in average life expectancy is indicated
next to the arrows Image from the discussed article in Nature Communications
The concentration of the drug in the blood plasma of the mice was approximately the same, that is, it was not a matter of how much they ate it or how it was absorbed into the body. Then the authors of the work suggested that the increased mortality of mice with short telomeres under the influence of rapamycin may be associated with an increase in the number of tumors. Typically, short telomeres prevent a cell from undergoing tumor transformation—the less it has left to divide, the more difficult it is to form a tumor. But rapamycin works as an immunosuppressant, that is, it suppresses the body's response to uncontrolled cell growth. It could be that rapamycin counteracts the effect of short telomeres and enhances tumor growth. But this is not so: after death, scientists did not find traces of carcinogenesis in any of the mice with short telomeres.
Apparently, something inside the animals' cells with short telomeres prevented rapamycin from working. This is supported by another observation that the researchers made: mice with telomerase deficiency did not lose weight when exposed to rapamycin. At the same time, in normal animals this happens invariably because rapamycin blocks the growth of adipose tissue.
One of the immediate effects that mTOR has on cells is to increase protein synthesis. Therefore, its activity can be assessed by the level of phosphorylation of ribosomal protein S6: the higher it is, the more intense the synthesis. In normal cells, rapamycin reduces S6 phosphorylation, inhibiting ribosome function. The researchers measured the concentration of phosphorylated S6 in mice that had already been on a regular or rapamycin diet for two months. It turned out that, unlike normal animals, rapamycin did not work in the liver of mice with short telomeres: the level of S6 phosphorylation, despite the administration of the drug, remained the same. The same thing happened with other potential effects of rapamycin: in mutant mice, it did not increase the level of autophagy (self-digestion) in cells and did not reduce the number of mitochondria - that is, it did not affect the metabolic rate in the cells. This means that rapamycin did not fulfill its main function - it did not block the mTOR signaling pathway.
To find out whether the drug really didn't work, the authors tested what happened in the liver cells of mice with short telomeres two hours after its administration. It turned out that within two hours, rapamycin reduces the amount of phosphorylated S6 - similar to what happens in normal animals. Thus, the problem was not with rapamycin itself. If it can do its job in cells, it may be that it simply isn't doing enough.
The researchers hypothesized that mTOR activity in cells from mice with short telomeres itself was so high that rapamycin could not reduce it. Indeed, when they compared the amount of phosphorylated S6 in normal and mutant animals, they noticed that it was consistently higher in mice with short telomeres. They then sequenced the RNA in the liver cells and found that animals with short telomeres had higher expression of genes that are associated with various metabolic processes - the breakdown of glucose, division and growth, the synthesis of proteins and fats - all of which are under the control of mTOR.
But if the mTOR pathway is so active in the cells of mice with short telomeres, and its blocker rapamycin shortens their lifespan, then mTOR may serve as a compensatory mechanism and mitigate the effects of telomerase deficiency. To test this hypothesis, the authors of the work created double knockout animals in which not only telomerase, but also S6 kinase (S6K), the protein that is responsible for S6 phosphorylation, did not work. Having measured their life expectancy, the researchers noticed the following pattern (Fig. 3). In animals with functioning telomerase, S6K knockout prolongs life because it acts similarly to rapamycin, blocking the effects of the mTOR pathway. In the first two generations of animals without telomerase, there is practically no difference in life length. But in the third generation of mice with short telomeres, S6K knockout, on the contrary, shortens life. Thus, with long telomeres, the mTOR pathway can be dispensed with, and its blockade works to prolong life. But with short telomeres, it becomes critical for survival.
Rice. 3.
Survival graph of mice with different sets of mutations.
In each pair, a darker shade indicates an animal with a functioning S6-kinase, and a lighter shade indicates an S6K knockout. Gray
- mice with working telomerase,
red
- first generation of mice without telomerase,
blue
- second,
green
- third.
The dotted line
represents the median lifespan: the time until which half of the population survives.
The red arrow
indicates a sharp decrease in lifespan in the third generation of telomerase knockout mice with S6K knockout.
Image from the discussed article in Nature Communications
Thus, the idea of using one weapon against several causes of aging at the same time has failed - at least the weapon chosen by the researchers is not suitable for it. By blocking mTOR, rapamycin prevents cells with short telomeres from surviving.
In the article discussed, the researchers only worked with mice, but humans also have diseases that are associated with severe shortening of telomeres. This is, for example, dyskeratosis congenita - a deficiency of telomerase, which first affects skin pigmentation, and then disrupts the functioning of the bone marrow, which leads to the death of patients. Rapamycin and its analogues will probably not be able to help such people, as well as mice with telomerase knockout.
At the same time, it is still completely unclear to what extent mTOR blockers will be useful for older people. It is known that the average length of telomeres in humans decreases with age, but will this become an obstacle to prolonging life with the help of rapamycin and similar drugs? Or will it be necessary to somehow act alternately with rapamycin and telomerase activators in order to achieve the desired effect? One way or another, it is already clear that there will be no simple answer to this question.
The story of rapamycin and telomeres is a revealing example of the problem facing modern aging science. Every time gerontologists discover some process that aggravates the aging of the body, and come up with a way to stop this process, it invariably reveals a reverse “positive” side. For example, shortening telomeres can be considered protection against cancer. Oxidative stress is a stimulus that prompts the cell to mobilize internal reserves to combat unfavorable conditions. And mTOR, in turn, saves cells when telomeres are too short. Therefore, we are unlikely to be able to declare one of the causes of aging as the main enemy once and for all and start a war against it. Instead of a decisive offensive, resourceful diplomacy will be required - weighing risks, alternating medications, searching for compromises that could prolong the life of the body without making it vulnerable to the next enemy.
Source:
I. Ferrara-Romeo, P. Martinez, S. Saraswati, K. Whittemore, O. Graña-Castro, LT Poluha, R. Serrano, E. Hernandez-Encinas, C. Blanco-Aparicio, JM Flores, MA Blasco.
The mTOR pathway is necessary for survival of mice with short telomeres // Nature Communications
. 2021. DOI: 10.1038/s41467-020-14962-1.
Polina Loseva
Rapamycin in life extension
Drugs that are prescribed to treat age-associated diseases such as hypertension, diabetes, prostate cancer, are similar to anti-aging agents in their inhibitory effect on cell hyperfunction triggered by mTOR.
Thus, metformin, which is prescribed to diabetics, prolongs the life of mice and worms. Aspirin reduces the risk of thrombosis and cancer of the digestive system.
Rapamycin is thought to exert its life-extending properties by mimicking the effects of caloric restriction, one of the most reliable ways to prolong life in animals. It targets the signaling molecule mTOR, which is an important node in nutrient sensing pathways. Lack of food turns off mTOR and activates emergency systems that allow us to survive periods of hunger.
These pathways trigger autophagy, the process by which cells engulf dysfunctional organelles and molecules for energy. This reduces the buildup of dead organic material that typically clogs our tissues as we age, and therefore slows down or even reverses the aging process.
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Clinical trials of rapamycin in humans are thought to be nearly impossible—it would take decades to detect any longevity effects.
Unfortunately, a drug like rapamycin intended to prevent respiratory disease in older patients has not been tested in clinical trials. The drug showed early promise and was thought to work by slowing immune aging, or age-related decline of the immune system. However, many other mTOR inhibitors are in development.
Rapamycin: a short but interesting story
Louis is 27 and works on an assembly line in Three Rivers, Michigan. And Charles is an ordinary 50-year-old family man with an average income from Atlanta. Van is 72 and retired. What do these three have in common besides their American citizenship? They all don't want to die and take the drug rapamycin, which they believe will slow down their aging. In Russia, biohackers almost never use rapamycin - but not because they don’t want to, but because it is, to put it mildly, a little expensive - from 450 rubles per tablet. But we can assume that in the future it will become cheaper, and then...
The first search for a cure for aging began thousands of years ago. Gilgamesh also tried to find a way to live forever. (The guy turned to the immortal old man who survived the flood and was sent by him... to the bottom of the sea to look for a certain type of coral. The search did not end particularly successfully - Gilgamesh has not been with us for a long time). Further, the ancient historian Herodotus wrote about a fountain that bestowed longevity, and in the Middle Ages the Holy Grail promised eternal life to brave knights. Since those epic times, a lot of water has passed under the bridge, but despite the fact that we have made great progress in understanding the world in comparison with Gilshamesh or the people of the Middle Ages, the recipe for immortality has never been found.
Activism for radical life extension is popular now. Adherents of the idea want to prolong a person’s healthy life using classical medicine methods. They advocate for the early start of human trials of anti-aging drugs, and therefore lobby for the recognition of aging as a separate disease. Biohackers, following them, begin to experiment on themselves with drugs that have shown effectiveness in the fight against old age in model animals. In this way, biohackers are trying to fill the gap caused by the lack of clinical trials and provide science with at least single examples of the long-term effects of certain drugs (and, of course, extend their lives!).
One such promising drug that has become a favorite of biohackers is rapamycin. And although it appeared in the doctor’s arsenal at the turn of the last and present centuries, its history as a potential cure for old age began a little later...
How to walk barefoot without getting tetanus
The history of rapamycin begins in 1965. Dr. Stanley Skoryna of McGill University, Montreal then convinced the WHO to provide funding for a pilot project to study the relationship between heredity, disease and nature on Easter Island. As a result, a Canadian research expedition to this island was organized. During its course, it was noticed that although the aborigines walked barefoot, they did not pick up tetanus and fungi. Scientists decided that the island's soil contained something special, and, having collected its samples, left them for storage in the university laboratory.
Easter Island. Historical engraving.
In 1975, with the support of Ayerst
(
Ayerst, McKenna and Harrison, Ltd.
) Surendra Nath Sehgal and colleagues went back to these samples and tried to find bacteria in them that secrete antifungal substances (the bacteria, by the way, can be stored frozen for many years).
The experiment was successful, and they stumbled upon Streptomyces hygroscopicus
(later renamed
S. rapamycinicus
), which secretes an antibiotic from the class of macrolides with an antifungal effect during its life.
The substance was named rapamycin after the name of the island in the local language - Rapa Nui
. But further research revealed that the substance has an undesirable side effect - it suppresses the immune system! (When you are being treated for fungal infections, immunosuppression is not what you want). As a result, he was forgotten, and the company's laboratory moved from Canada to Princeton University, New Jersey. But Surendra Nath Sehgal’s interest in rapamycin was so great that before moving, he prepared the substance in large quantities, knowing that in the new place he would not have the components and conditions, and brought it with him.
In 1987, when immunosuppressants were used to suppress the immune response in organ transplants, researchers from a Canadian company returned to rapamycin. A surprise awaited them: in clinical trials, it turned out to be more powerful (up to 100 times) and less toxic as an immunosuppressant than cyclosporine A, which was used at that time. This gave rise to a whole line of research. By 1999, it was proven safe to use in humans, and the F.D.A.
approved this substance.
Pfizer
patent , the drug was produced under the name rapamune, and the active substance was given a second name adopted by the United States Adopted Names Council - sirolimus.
But there was another direction of research. Back in the 1990s, Michael Nip Hall and his colleagues at the University of Basel (Universität Basel) took on the project of describing the fungicidal effect of a substance at the cellular level. Joe Heitmann, a postdoc at the University of Basel, grew a normal yeast culture and placed it in a petri dish that had been pre-coated with rapamycin. Most of the yeast died, but some mutated yeast cells survived. Heitman identified a total of approximately 20 different mutations that confer resistance to rapamycin. All these mutations occurred in three different genes encoding FKBP
and two others from a class of kinases later named
TOR1
and
TOR2
and collectively called
TOR
(for Target of Rapamycin, target of rapamycin binding). For more information about the cellular chemistry of rapamycin, you can watch the lecture at the link.
By observing the processes in which the protein is involved, the researchers noticed that fruit flies with reduced TOR activity, like individuals of other species with this feature, are smaller in size than their counterparts without mutations. At first, most of those working on the topic tended to believe that these animals simply had fewer cells and that TOR influenced the processes of cell division. That is, the gene mutation and weakening of the protein activity, in their opinion, should have had a cytostatic (stopping the growth of the number of cells) effect. But there was no exact answer, so Thomas Neufeld at one point set out to clarify what TOR
: for cell size or number of cell divisions.
To do this, he counted the number of cells in individual sections of the wings of flies with and without the mutation and then extrapolated this proportion to the entire body of the fly. The number of cells of two flies, large and small, turned out to be the same! Therefore, he concluded that the difference in size between normal and mutant flies is determined precisely by the size of the cells, and not by their number. That is, the TOR
controls cell growth, although previously it was believed that nothing controls it and it occurs spontaneously.
Next, experiments began to further elucidate the mechanisms of TOR in mice and even in human cell cultures. Soon the mTOR
(mammalian TOR, TOR protein in mammals), even two,
mTORC1
and
mTORC2
(
the C
in these abbreviations stands for the word
complex
), and only the first turned out to be sensitive to rapamycin.
And while both are controlled by growth factors, mTORC1
also responds to nutrient levels, amino acid levels, energy levels, and oxygen levels.
Do more, do better!
Research into rapamycin has continued since the 1990s, and has increased even more since 2012 as Pfizer's
and many companies were interested in producing the drug.
What were the areas of research? First, they looked for new bacteria that would produce more of the substance. An example of such research: in 1995, scientists from Japan, Shizuka Prefecture, found a new bacterium, Actinoplanes sp.
, which produced ten times more rapamycin than
S. rapamycinicus
. Research is also being conducted in the field of genetics: which gene clusters in which bacteria are responsible for greater or lesser production of rapamycin.
Secondly, there is a search for an effective way to produce rapamycin, since now this is a very expensive and labor-intensive process, which significantly increases its price. Scientists are researching what to “feed” the bacteria, at what temperature and acidity to keep it in order to “milk” more substance from it. For example, if you place it in an environment rich in fructose, you will be able to extract quite a lot of rapamycin, but not the maximum amount possible. At the same time, creating a favorable environment in a bioreactor should not be too difficult. By the way, recently, to study the effect of nutrients on the production of rapamycin, neural networks were used in conjunction with another methodology, which helped researchers understand that the bacterium's appetite is perfectly satisfied by mannose, L-lysine and soybean meal, presented in a certain concentration. As a result of the production of rapamycin by the bacterium S. hygroscopicus
reached 320.89 mg/l. You can read more about current methods of rapamycin biosynthesis at the link.
Scientists are also looking for new functional analogues of rapamycin, the so-called. rapalogues, which, like rapamycin, inhibit mTOR
.
Many new rapalogues have been produced through biological modifications. Novartis fungi
known to undergo biotransformation and thus found several rapalogues (39-O-demethylrapamycin, 27-O-demethylrapamycin, 16-O-demethylrapamycin). Different rapalogues may have a more targeted effect on a particular disease, for example, different types of malignant tumors, or are better absorbed. For example, emsirolimus is better absorbed than the original rapamycin.
Rapamycin in life extension
First attempts to study how the mTOR
, and accordingly rapamycin, are associated with life expectancy, dating back to the 2000s.
Early experiments of this kind were carried out on brewer's yeast, as well as on invertebrates - worms and fruit flies. It was then discovered that mutations in the TOR
extended the lifespan of these animal models. The next important step was to demonstrate this effect in mammals.
In 2009, David Harrison and colleagues from various US research universities began experimenting on laboratory mice. These were intended to be "middle-aged" animals, but due to difficulties in formulating a feeding protocol, the experiment began quite late in the mice's lifespan - when the mice were 20 months old, roughly equivalent to 60 years in humans. Each laboratory involved in the study, of which there were three, conducted experiments in parallel using the same protocol. A total of 2,000 mice took part in the study. The scientists made sure that the mice were genetically diverse to avoid the effect that they would all accidentally be more susceptible to the drug than the population average (this is possible with genetically homogeneous laboratory animals). The rodents were given rapamycin as a supplement along with food at a dosage of 2.24 mg per kilogram of weight (assuming that the standard weight of an average laboratory mouse is 20 grams, then each individual was given 0.0446 mg of the substance). As a result, the lifespan of the mice was extended by 14% compared to the control group. This was previously only possible through a calorie-restricted diet. It was then that it was first suggested that calorie restriction, known to prolong the life of animal models, and rapamycin work in the same way - by involving the mTOR
. But there were also doubts - during the fasting protocol, mice usually lost weight, and it only worked if the mice were put on a diet from the very beginning of life. Only much later did they discover that TOR activity is regulated by the amount of available nutrients.
There is also evidence, although so far only indirect, in favor of the fact that rapamycin is capable of extending human life. Let's start with the fact that if we describe the potential and registered clinical applications of rapamycin and rapalogues, we will have to remember a number of diseases. It has the following potential uses:
- In the fight and prevention of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases (research is at the preclinical testing stage), it is potentially useful as a neuroprotector;
- In the prevention and treatment of certain types of cancer, such as tumors of the intestines, kidneys, brain, lymph nodes. Rapamycin is thought to be beneficial because increased mTORC1
. It has also shown benefit in many preclinical trials, and a number of phase I and II clinical trials are currently underway; - In the treatment of cardiovascular diseases - for the prevention of heart attack, fibrosis and repeated stenosis of the arteries. Potentially reduces the cardiotoxicity of antiretroviral drugs used, for example, in HIV therapy. Most of the research is in the preclinical phase;
- As an anti-inflammatory agent in rheumatoid arthritis (where other NSAIDs do not provide sufficient pain relief), it reduces inflammation in lupus erythematosus. Data for autoimmune diseases are based on observing patients taking the drug for immunosuppression and comparing their results with those of the general population;
- For skin rejuvenation (in the form of an anti-aging skin cream, currently in clinical trials), teeth (tests on mice);
- Rapamycin may help fight obesity (preclinical phase).
Many of these diseases are associated with old age. The older we are, the higher the likelihood of heart attack, stenosis, malignant tumors, Alzheimer's and Parkinson's. “Maybe, if this drug prolongs the life of laboratory animals and counteracts diseases associated with old age, it is a cure for old age? “You can hear something like this from enthusiasts of radical life extension: “The effect is achieved due to the fact that rapamycin slows down the cell cycle.” Michael Blagosklonny, an oncologist and gerontologist at Roswell Park Comprehensive Cancer Center and a rapamycin enthusiast, even states in his article that the decision not to take rapamycin will have the same impact on life expectancy as the decision to continue smoking. ! But there is no serious clinical evidence for such claims.
The Dog Ageing Project was launched in 2014
- a massive trial of the effects of rapamycin on the lifespan of domestic dogs. Both young and old dogs of different breeds can participate in the project. Once the study is completed, we will have more reason to believe that rapamycin has a chance of extending healthy life in humans. Or not.
The cunning of rapamycin
the FDA as generally safe for use in humans.
back in 1999. There are no documented cases of death from rapamycin overdose—even in a failed suicide attempt in which an 18-year-old girl took 103 1 mg rapamycin tablets, the only effect found was an increase in total blood cholesterol.
But when the drug was registered with the FDA
, the registration came with a warning that all immunosuppressive drugs “because they suppress the immune system, may increase a person's susceptibility to infections and may contribute to the development of tumors such as lymphoma and skin cancer.” In principle, everything is logical: the worse the immunity, the worse it attacks mutant, for example, cancer cells. But clinical practice refutes such logic. Mikhail Blagosklonny argues that the immunosuppressant label has pushed public interest away from the drug for a long time.
It is true that rapamycin can increase the severity of bacterial infections because it inhibits neutrophil function and also causes mild thrombocytopenia, anemia, and leukopenia (low platelet, red blood, and white blood cell counts, respectively). It slows down the processes of cell division, therefore there are fewer blood cells in the body.
Other unpleasant side effects include stomatitis and mycositis (ulceration of the mucous membranes of the mouth and digestive tract). A rare side effect of rapamycin is non-infectious interstitial pneumonia. But these side effects are reversible, and if they do not interfere with life, then proponents of longevity argue that “there is nothing to worry about” and the benefits outweigh the harm, and if they interfere, “you can simply reduce the dose.” In order to prevent aging, according to Blagosklonny, rapamycin can be used either periodically (for example, once a week) or in low daily doses, and can be discontinued if any unpleasant side effects occur.
There was a lot of controversy around such a side effect as the development of temporary diabetes. It may be recalled here that fasting, which has a similar effect on aging as rapamycin, also causes insulin resistance in both mice and humans. Both of these interventions work in a similar way: mTOR is generally activated more the more nutrients there are in the environment. The logic behind this is that during prolonged fasting, glucose use in non-brain tissues must be suppressed to ensure an adequate supply of energy to the brain. A starvation diet, although it causes diabetes, is not considered harmful, so diabetes caused by rapamycin should not be considered harmful. In the end, you can simply supplement rapamycin with metformin, another potential geroprotector, and eliminate the symptoms of diabetes - something like this is what Mikhail Blagosklonny says in his article. (The position of the editors does not necessarily coincide with this point of view.)
Conclusion
Currently, there is no clear conclusion from scientists whether rapamycin is suitable or not for the role of the elixir of youth. Someone rushes to proclaim it practically a panacea, someone warns: “But the side effects, like the effect itself, have not yet been fully studied!” Most likely, the truth is somewhere in the middle: on the one hand, we know quite a lot about the substance, including from clinical practice. On the other hand, there is no guarantee that rapamycin will work as well in humans as it does in mice or dogs.
At the moment, a lot of human trials are being conducted that will help answer many questions about this drug. But all these studies concern only certain diseases, and most do not concern the problem of aging itself. Therefore, the best thing to do now is to lobby for recognition of aging as a disease and thus allow clinical trials of rapamycin and other anti-aging drugs in humans.
Until we have such trials, we will be content with the examples of isolated daredevils such as Van, Charles and Louis, as well as medical practitioner Dr. Alan Green from the USA, who prescribes rapamycin to his patients to treat old age and takes it himself.
Literature
Yoo, Y. J., Kim, H., Park, S. R. et al. An overview of rapamycin: from discovery to future perspectives. J Ind Microbiol Biotechnol 44, 537–553 (2017). https://doi.org/10.1007/s10295-016-1834-7
Patel, G. K., Goyal, R. and Waheed, S. M., 2021. Current Update on Rapamycin Production and Its Potential Clinical Implications. High Value Fermentation Products, Volume 1: Human Health, p.145.
Rapamycin and youthful skin
A study conducted by a team at Drexel University College of Medicine in Philadelphia (USA) showed that the immunosuppressant rapamycin also has anti-aging effects on human skin.
The clinical trial involved 13 volunteers over 40 years of age. They applied rapamycin cream to the back of one hand and placebo cream to the back of the other hand every 1-2 days before bed.
Participants attended assessment visits every 2 months for 8 months. During visits, researchers took photographs of their hands to evaluate skin wrinkles and overall appearance.
Regular application of rapamycin to the back of the hands has been found to reduce wrinkles and sagging, and improve skin tone.
After 8 months, the arms of most participants treated with rapamycin showed an increase in collagen and a decrease in p16 protein, an indicator of cellular aging. Skin with more of these cells becomes more wrinkled and heals more slowly.
After 8 months, most hands treated with rapamycin showed increased collagen and lower levels of an aging marker in skin cells compared to those using a placebo.
In this case, rapamycin treatment demonstrated clear effects on skin aging at both molecular and clinical levels.
However, the scientists note that these results are just the early stages of their research, and they need to do much more before they can say how best to use rapamycin to slow aging.
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Brief conclusions
- The immunosuppressant rapamycin appears to have antiaging properties;
- In experiments on mice, the drug showed an increase in their life expectancy;
- Rapamycin has also demonstrated anti-aging effects on human skin;
- However, in order to start using it as an anti-age drug, additional observations are necessary to exclude and minimize possible risks.
