What are the functions of Rapamycin? (I)

Rapamycin (RAPA), also known as “sirolimus”, was first discovered by scientists in the soil of Easter Island, Chile in 1975 due to its strong antifungal properties. Rapamycin is a macrolide antibiotic. It is similar in structure to FK506 but has a very different immunosuppressive mechanism. FK506 inhibits the proliferation of T lymphocytes from G0 to G1, while RAPA blocks signaling through different cytokine receptors, blocking the progression of T lymphocytes and other cells from G1 to S. Compared with FK506, RAPA can block calcium- and calcium-independent signaling pathways of T and B lymphocytes.

In view of the strong immunosuppressive effect of rapamycin in clinical trials, it can replace cyclosporine with a clinical history of more than 30 years. And compared with cyclosporine, rapamycin oral solution has a smaller dose (only 2 to 3 mg each time), stronger anti-rejection effect, and fewer side effects. Since its launch, rapamycin has quickly become a common oral immunosuppressant for organ transplant around the world.

Now, scientists have recently discovered that rapamycin can be used to treat Alzheimer’s disease. Some experiments also show that rapamycin can restore the ability to remember in experimental mouse models. In brief, over the past 30 years, rapamycin has attracted great attention from scientists due to its potential in anticancer, neuroprotective, and anti-aging therapies. However, more functions of rapamycin are gradually being discovered. Let’s take a quick look.

  1. Geroscience: Rapamycin may be able to delay skin aging!

doi: 10.1007 / s11357-019-00113-y

In the pursuit of eternal youth, people are often obsessed with lotions, supplements, serum and diet, but a new discovery may give us new options. A study published by researchers at Drexel University School of Medicine in Geroscience showed that rapamycin, an FDA-approved drug that is commonly used to prevent organ rejection after transplant surgery, may also slow the aging of human skin.

The study shows that after using rapamycin cream on hand for eight months, the collagen was increased, and the level of p16 protein was significantly reduced. P16 protein is a key indicator of skin cell aging. So how does rapamycin work? Mechanistically, rapamycin can block the appropriately named “rapamycin target” (TOR), which plays a signaling role in human cell metabolism, growth, and aging. When studying p16 protein more deeply, it was found that rapamycin’s ability to improve human health is not just about staying young: when cells have mutations that would otherwise cause tumors, specific responses can help prevent tumors by slowing the cell cycle.

  1. Prion: new approach to fight prion disease.

doi: 10.1080 / 19336896.2019.1670928

Many potential therapeutic compounds target the misfolded protein with replication capabilities: prions. In a new study, Abdulrahman and colleagues hypothesized that combination therapy could be used to synergistically target different aspects of prion disease. Their goal is to target the prion itself using cellulose ethers and to target the autophagy pathway that degrades prions using a PDK1 inhibitor (AR12 or rapamycin), which has the ability to activate autophagy activity. When administered alone, both types of compounds have been shown to have the potential to prolong life in mice. However, combination therapies have not brought any additional advantages. Mice treated with both types of compounds died simultaneously with mice treated with a single compound. In further research, they found that cellulose ethers inhibited autophagy activity of AR12 and rapamycin. As a result, it appears that only the benefits of cellulose ethers are apparent in mice.

Although it is disappointing that this combination therapy cannot work synergistically, this study highlights some important aspects that must be considered in future treatment design. Since few drugs used to treat neurodegenerative diseases show promise for life extension, drug-drug interactions are almost completely unknown, but Abdulrahman and his team have confirmed the need to study these phenomena. With the right combination therapy, their approach still provides an effective complementary therapy for prolonging the life of patients with prion diseases.

  1. Aging Cell: Rapamycin may effectively inhibit age-related degradation of brain function.

doi: 10.1111 / acel.13057

Recently, in a research report published in Aging Cell, scientists from the San Antonio Healthcare Center and other institutions found that the drug rapamycin may improve the age-related reduction of cerebral blood flow (to the brain) and memory loss. These related research results are critical to developing new therapies that effectively inhibit or treat Alzheimer’s disease.

In this study, researchers began to add low-dose rapamycin to their diets when rats were 19 months old. Rapamycin therapy in daily food continued until rats were 34 months old, and the researchers found that even though the rats were very old, the blood circulation in their brains was exactly the same as when they started treatment. Untreated elderly rats were observed to have blood loss to the brain and memory loss.

TOR, the target of rapamycin, is the main controller of cell growth and aging. Researchers have found that during the aging process of the body, TOR can drive the loss of synapses and decrease blood flow in the brain. Synapses can connect different neurons, and the brain relies on neurons to send and receive signals. Researchers say that the brain consumes a lot of energy but has no substitute resources. Neurons need glucose and oxygen to maintain their functions, and blood vessels can provide them with nutrients. Finally, the researchers said that they will continue to study in depth to clarify the molecular mechanism of rapamycin’s inhibition of age-related cerebral vascular deterioration.

  1. Science journal: Rapamycin can help treat beta-thalassemia.

doi: 10.1126 / scitranslmed.aav4881

In a new study, researchers from the United States and Italy have discovered that autophagy-activated kinase ULK1 plays a key role in clearing accumulated alpha-globin in mouse models of beta-thalassemia and cells from beta-thalassemia. They also found that the lack of ULK1 reduced autophagy clearance of alpha-globin in red blood cell precursors and exacerbated the phenotype of the disease. However, inactivation of the classic autophagy-associated gene 5 (Atg5) resulted in relatively small Impact. The relevant research results were published in the journal Science Translational Medicine on August 21, 2019, and the title of the paper was “The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia”.

Systemic treatment with the mTOR inhibitor rapamycin can promote the accumulation of α-globin clearance and alleviate conditions in a mouse model of β-thalassemia by activating the ULK1-dependent autophagy pathway. Similarly, rapamycin reduces the accumulation of free alpha-globin in red blood cells derived from CD34 + cells in patients with β-thalassemia.

  1. Aging: Rapamycin can delay epigenetic aging

doi:10.18632 / aging.101976

In 2018, Steve Horvath of the University of California, Los Angeles (UCLA) and Ken Raj of the British Public Health Department developed an improved algorithm called Skin and Blood Clock, which is suitable for both in vitro and in vivo cultured cells. Using this epigenetic clock, Raj and Horvath have now demonstrated that rapamycin has the effect of delaying aging, not only for many animal species but also for human cells.

The life-extending properties of rapamycin may be the result of multiple effects, including but not necessarily limited to inhibiting cellular senescence and epigenetic senescence, and may enhance cell proliferation potential.