In the middle of the South Pacific Ocean lies a remote and mysterious island, Rapa Nui, better known as Easter Island. The island is 2,200 kilometres from its nearest inhabited island, and its inhabitants have never been infected with tetanus in their history. This phenomenon is of great interest to the scientific community.
In 1964, scientist Georges Nográfy and his research team set foot on the land to explore the secrets behind this "magical" phenomenon. They carefully collected soil samples from different areas of the island and brought them back to Canada for in-depth analysis. After five years of unremitting efforts, the researchers discovered a special species of Streptomyces in these soil samples, Streptomyces hydrosatrium, which can produce large quantities of a compound that was not known to the scientific community at the time, and the researchers named this newly discovered compound rapamycin [1].
Fig.1 Easter Island, the place where rapamycin is manufactured, was isolated for the first time
The transition from antifungal to pleiotropic therapy and its prospects
Rapamycin is a class of macrolide antibiotics originally developed as an antifungal drug. As the research deepened, the scientists were pleasantly surprised to find that it exhibited immunosuppressive and antiproliferative properties in mammalian cells. Based on these findings, rapamycin has been used as an immunosuppressant since 1999, especially in kidney transplant patients. This shift not only broadens the scope of clinical application of rapamycin, but also marks its important position in the field of organ transplantation.
Fig.2 Wyeth designed a monument on Easter Island in 2011 to commemorate the discovery of rapamycin
In humans, the mammalian target rapamycin (mTOR) signaling pathway plays a key role in cell growth and metabolic regulation. When the mTOR signaling pathway is dysfunctional, it can lead to a range of diseases, including but not limited to cancer, diabetes, obesity, neurological diseases, and certain genetic diseases. Rapamycin (rapamycin or sirolimus) and its derivative (everolimus) are a class of inhibitors that specifically target the mTOR signaling pathway. By inhibiting the activity of mTOR, it is able to regulate the growth, proliferation, and metabolism of cells, thereby playing a role in the treatment of a variety of diseases. Recent studies have shown that rapamycin not only has immunosuppressive effects, but also shows multiple anti-tumor and anti-aging effects, which makes it an all-rounder in medical research and is known as a model of "one drug with multiple effects". This pleiotropic feature makes rapamycin have a wide range of potential in clinical application, not only in the field of organ transplantation, but also in the field of tumor treatment and anti-aging.
Fig.3 "One drug with multiple effects" of rapamycin
With the deepening of the understanding of the mTOR signaling pathway, rapamycin and its derivatives are expected to provide new strategies and methods for the treatment of more diseases. As a drug with multiple pharmacological effects, rapamycin has far more effects on the human body than kidney transplant patients. Here are a few important therapeutic effects of rapamycin that provide new perspectives for the treatment of different diseases:
1. Rapamycin's renal protective effect and clinical application recommendations
Chronic transplant kidney injury is a major obstacle to long-term survival of transplanted kidney in kidney transplant patients. In clinical practice, this impairment is manifested by a gradual decline in renal function, mainly characterized by renal interstitial fibrosis and tubular atrophy. This progressive loss of kidney function often results in patients requiring more frequent medical intervention and possibly re-dialysis. Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are commonly used immunosuppressive drugs after organ transplantation. However, long-term use of CNIs may lead to drug toxicity, which is an important factor in the pathogenesis of chronic transplant kidney injury. CNIs reduce the risk of rejection by inhibiting T cell activation and proliferation, but they may also cause kidney damage. In addition, kidney injury is also a common complication after liver transplantation, which not only affects the immediate treatment effect of patients, but also may have a serious impact on the long-term survival of patients. The occurrence of acute kidney injury and chronic kidney disease after liver transplantation is related to a variety of factors, among which CNI drug toxicity is a risk factor that cannot be ignored.
The results of animal studies have shown that rats treated with CNIs have significant infused glomerular arterial injury and proximal tubular malformations compared with controls treated with olive oil [2].
Fig.4 Changes in the glomeruli of rats after CNI drug (cyclosporine) treatment
The metabolic process of rapamycin mainly relies on the cytochrome P450 3A4 (CYP3A4) isoenzyme in the cells of the liver and intestinal wall. This enzyme metabolizes rapamycin so that it can be finally excreted through the digestive system, with most of the drug (about 97.8%) excreted in the feces and only a small amount (about 2.2%) in the urine. In addition, rapamycin can regulate the mesenchymal transition of renal tubular epithelial cells, help reduce renal interstitial fibrosis, and protect and improve renal function in liver transplant recipients to a certain extent[3].
In the latest Chinese Expert Consensus on the Clinical Use of Rapamycin Target Protein Inhibitors in Liver Transplant Recipients (2023 Edition), based on current medical evidence and clinical experience, experts make the following recommendations: For liver transplant recipients with renal insufficiency due to the use of calcineurin inhibitors (CNIs), a combination of mTOR inhibitors (eg, rapamycin) and low-dose CNI is recommended [3]. According to the Guidelines for Immunosuppressive Treatment of Kidney Transplant Recipients in China (2016 Edition), for patients with chronic transplant kidney injury with specific conditions: the estimated glomerular filtration rate (eGFR) is greater than 40 mL/(min·1.73 m²); At the same time, mTOR inhibitors are recommended as an alternative to CNI in recipients with a proteinuria/creatinine ratio of < 500 mg/g (or other equivalent proteinuria assessment) [4].
Figure 5 Relevant guidelines and consensus recommendations
2. Evaluation of the clinical potential and safety of rapamycin in the dual effects of anticancer and immunosuppression
Rapamycin is an immunosuppressant with multiple pharmacological effects, which binds to FK506-binding protein-12 (FKBP-12) upon entry into cells, specifically inhibiting the activity of mTORC1. mTORC1 plays a key role in cell growth and proliferation, and rapamycin exerts its pharmacodynamic effects by inhibiting this complex[5].
Fig.6 mTORC1 pathway: rapamycin inhibits mTORC1,
Enhances intracellular protein clearance and autophagy
This mechanism is particularly important in cancer cells, whose infinitely proliferating properties make their need for nutrients and energy much higher than normal cells. To meet this high demand, cancer cells undergo significant changes in nutrient absorption and energy metabolism, a process that is regulated by the mTORC1 pathway. As a result, an increase in mTORC1 activity has been observed in many cancer patients, which opens up the possibility of rapamycin therapy.
In organ transplant patients, long-term use of immunosuppressants may increase the risk of tumorigenesis, particularly CNIs such as cyclosporine, which have been shown to promote tumor metastasis in animal trials [6]. However, different immunosuppressant regimens have varying effects on tumorigenesis, and one observational study suggests that rapamycin-containing regimens may reduce tumor risk [7].
Fig.7 Cyclosporine can promote lung metastases of renal cell carcinoma in mice
Currently, everolimus, a derivative of rapamycin, has been approved by the FDA for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors and advanced breast cancer. Everolimus has been shown to significantly improve progression-free survival in patients with advanced pancreatic neuroendocrine tumors in clinical studies [8-9]. In addition, multiple clinical trials evaluating the potential efficacy of rapamycin and its derivatives for other cancers such as thyroid cancer, ovarian cancer, diffuse large B-cell lymphoma, endometrial cancer, etc., are ongoing.
Fig.8 Inhibition of tumor microenvironment (TME) by rapamycin
Essential for its antitumor activity
In terms of safety, studies have shown that rapamycin side effects, such as fatigue (fatigue), in cancer and transplant patients, are often caused by the disease itself. In a controlled study of healthy volunteers and older adults, side effects were reported lower in the rapamycin group than in the placebo group, showing a favorable safety profile [10]. In addition, in placebo-controlled studies of healthy older adults, no significant differences in side effects were found in the rapamycin group compared with the placebo group [11]. In summary, rapamycin and its derivatives have shown great potential and value in the field of anticancer and immunosuppressive therapy. With the continuous deepening of clinical research, we expect these drugs to bring hope and improvement to more patients.
3. From longevity to anti-aging potential
Scientific Exploration and Clinical Evidence
As early as more than ten years ago, rapamycin was widely recognized as one of the "Top Ten Scientific Breakthroughs in 2009" by CCTV because of its significant role in prolonging the life span of organisms. The importance of the mTOR signaling pathway as a key factor in regulating lifespan has become increasingly prominent, and scientific studies have shown that inhibition of mTOR signaling through gene editing or drug intervention can effectively prolong the lifespan of invertebrates such as yeast, nematodes, and fruit flies [12]. In fact, at least 5 of the 12 features of human aging are regulated by mTOR [13].
In 2022, researchers at Harvard Medical School published a breakthrough study in Science Advances (IF=13.6), an authoritative journal, confirming that taking rapamycin can significantly extend the lifespan of mice. This discovery not only provides strong evidence for the anti-aging potential of rapamycin, but also points out a new direction for future research directions to delay aging and improve quality of life.
Figure 9 Study published in Science Advances
In this study, mice within 45 days of age were treated with rapamycin versus placebo. After the expiration of the treatment period, these mice were transferred to a regular chow diet and followed for life.
The tracking results showed that the mice treated with rapamycin grew slower and were relatively smaller. Further anatomical analysis revealed that the weight of the major organs such as the brain, liver, kidney, and spleen of these mice was reduced. In addition, there was a delay in the age at which these mice reached sexual maturity. However, there was no significant difference in the number of offspring between the two groups.
In terms of lifespan, the average lifespan of mice in the rapamycin group was 10% longer compared to the placebo control group (P = 0.036), a result that was particularly pronounced in male mice (P = 0.0064), while no significant difference was observed in female mice.
Fig.10 The lifespan of rapamycin-treated mice was extended by 10% compared with the control group
In addition to the prolonged lifespan, the degree of weakness in the later years of the rapamycin-treated mice was significantly lower than that in the control group (P=0.037). Specifically, the forelimb grip strength was stronger, gait disorder was reduced, physical condition score was improved, and abdominal distension was effectively controlled in the rapamycin-treated group.
These findings provide a strong experimental basis for rapamycin as a potential anti-aging drug, and open up a new perspective for future research directions to delay aging and improve the quality of life of the elderly.
Fig.11 The weakness of rapamycin-treated mice (green line) was lower than that of the control group (yellow line)
summary
In addition to its proven efficacy in prolonging life and improving quality of life in old age, the potential of rapamycin in the treatment of a variety of age-related diseases is being actively explored. These conditions include, but are not limited to, erectile dysfunction, amyotrophic lateral sclerosis (ALS), obesity, disc degeneration, osteoarthritis, and inflammatory bowel disease. At present, some studies have achieved encouraging preliminary results.
With the deepening of research, the "one drug with multiple effects" characteristics of rapamycin have gradually emerged, which not only provides a new choice for the existing treatment options, but also provides more scientific basis and treatment ideas for future clinical treatment. It is believed that in the near future, rapamycin will play its unique therapeutic role in a wider range of disease areas, bringing more hope and choice to patients.
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