Recent studies have shown that rapamycin is the only drug that consistently improves lifespan in mammals.
As recently as 2009, researchers believed that aging was simply untreatable, or that only growth factors could influence the seemingly inexorable process. Two scientific approaches were available to him that could slow aging. It is dietary restriction and/or growth factor restriction by genetic means. In general, these approaches were considered unsuitable for use in humans, as people are not very fond of dietary restrictions or having their genes tampered with.
However, the aging problem still remains, and to overcome this, the National Institute on Aging has established a program to identify compounds that can be rigorously tested for aging under a set of standard conditions. [1]. The goal of this program was to examine the effects of drugs on lifespan in genetically heterogeneous male and female mice.
Longevity.Technology: The new Interventional Testing Program (ITP) includes three geographically separated laboratories and is designed to make test mice genetically heterogeneous, involving both sexes. , is advantageous. Additionally, the site director was an expert in rodent aging research. ITP has been reported to be very successful to date, with about 64 different compounds being tested or being tested. Ten of these compounds have been reported to extend lifespan.
new research in experimental gerontology Analyzing the ITP 2009 trial of the drug rapamycin, authors Zelton Dave Sharp and Randy Strong consider what the effects of rapamycin can tell us about aging and the mechanisms of rapamycin itself.
Rapamycin is a macrocyclic lactone (product or chemical derivative of soil microorganisms) that was first isolated from soil samples obtained from Easter Island by Georges Nogradi in the late 1960s. [2]. Rapamycin was observed to inhibit eukaryotic cell proliferation, and the mechanism was subsequently investigated. This led to the discovery of the rapamycin target protein (TOR) in yeast responsible for growth inhibition. In addition, researchers also discovered his mammalian counterpart, mTOR, in 1994.
TOR is a (funny term) serine/threonine protein kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. [3]. Initially, yeast TOR1 and TOR2 were thought to regulate the cell cycle, but recent studies on the role of TOR in senescence have shown that deletion or inactivation of TOR by rapamycin results in partial cell cycle arrest. and the starvation phenotype, i.e., starvation. Better than I expected. Such findings suggest that chronic rapamycin may act as a potential anti-aging compound that mimics dietary restriction.
The researchers also pointed out that cell and organism size is another factor that may determine lifespan. They reported that long-lived Snell pituitary dwarf mice have the same number of skeletal muscle fibers as wild type. However, the fiber size of pituitary dwarfs was found to be smaller compared to wild type. This indicated that pituitary dwarfs lack growth hormone due to the reduced mTOR activity observed in muscle and liver.
Although rapamycin is a dangerous drug for chronic use in humans, it is still used to treat cancer and to suppress graft rejection. This led ITP to test the role of rapamycin in aging. This test required administration of encapsulated rapamycin to 20-month-old male and female mice. They reported that rapamycin helped mice live longer and healthier, with females benefiting the most.
How does rapamycin work?
The mTOR genes, mTORC1 and mTORC2, are structurally and functionally conserved in eukaryotes, including plants. A defining feature of mTOR is the FK506 binding protein (FKBP)-rapamycin binding (FRB) region located at the N-terminus of the kinase domain and interacting with the FKBP12-rapamycin complex. Evolution of FRB occurred to interact with phosphatidic acid (PA), which acts as a ‘gatekeeper’ for FRB interactions, activating and stabilizing the mTOR complex. [1].
Interaction with the FKBP12-rapamycin complex inhibits mTOR and prevents translation of TOR pathway components, thereby extending lifespan.
Effects of chronic rapamycin on age-related diseases
Several studies in mice have reported that chronic rapamycin slowed aging and ameliorated some age-related phenotypes. However, mice receiving these treatments also reported two adverse outcomes: nephrotoxicity (rapid deterioration of renal function) and testicular degeneration (which looks pretty bad). A 2014 study showed that chronic rapamycin inhibits cancer rather than slows aging, and since then there has been an increase in research on the role/mechanism of rapamycin or sirolimus in cancer therapy. Check the numbers on PubMed.
Previous studies in the Rb1+/- neuroendocrine tumorigenesis model showed that dietary restriction had little effect on tumor prevention and survival. However, treatment with rapamycin was shown to extend lifespan and delay tumor development. In addition, another study reported that enterally administered rapamycin could slow the progression of colorectal cancer and extend lifespan in certain mice. [1]. Several other clinical trials are underway to examine the effects of rapamycin on cancer. Also, some studies have shown that rapamycin not only prevents age-related diseases, but may also promote longevity benefits.
Although most studies have shown rapamycin to be beneficial as an anti-aging agent, some studies have reported adverse results. Rapamycin was reported to increase mortality in a mouse model of type 2 diabetes as a result of purulent inflammation. Another study reported adverse events with intravitreal administration of sirolimus in age-related macular degeneration (AMD).
next step
The authors note that several studies have observed that chronic rapamycin reduces the hallmarks of aging, stating: [1]”
Although rapamycin has been observed to prevent age-related diseases and promote health, the authors say more research is needed to determine the precise role of the mTOR system in aging and its diseases. claim. Sharp and Strong are particularly interested in ongoing research into the effects of rapamycin on the common marmoset, a non-human primate, which provides “important information for clinical application.” We hope to provide
[1] https://www.sciencedirect.com/science/article/pii/S0531556523000876
[2] https://link.springer.com/article/10.1007/s11357-020-00274-1
[3] https://www.sciencedirect.com/science/article/pii/S0014579310000360
