Rapamycin and its role in aging

Recent research indicates rapamycin to be the only drug that improves mammalian longevity consistently.

As recently as 2009, researchers believed that aging was simply not treatable or, if it were, only growth factors would be able to have any impact on the seemingly-inexorable process. Two scientific approaches were available that could delay aging – restrictions of diet and/or growth factors by genetic means. People generally aren’t wild about restricting their diet or having their genes fiddled with, so these approaches were deemed to be unsuitable for use in humans.

But the problem of aging remained, and in an effort to overcome this, the National Institute of Aging established a program for the identification of compounds that could be rigorously tested for aging under a series of standard conditions [1]. The goal of the program was to determine the effects of the drug on the lifespan of genetically heterogeneous mice of both sexes.

Longevity.Technology: The new intervention testing program (ITP) is advantageous since it included three test sites that were geographically separated, the test mice were designed to be genetically heterogeneous and involved both sexes; in addition, the site directors were experts in aging studies in rodents. ITP has been reported to be extremely successful to date, with about 64 different compounds tested or in the process of testing. Among them, 10 compounds have been reported to increase lifespan.

A new study in Experimental Gerontology analyzed the ITP 2009 test of the drug rapamycin and the authors Zelton Dave Sharp and Randy Strong ponder what the effects of rapamycin can tell us about aging – and the mechanism of rapamycin itself.

Rapamycin is a macrocyclic lactone (a product or chemical derivative of soil microorganisms) that was first isolated from soil samples obtained from Easter Island by Georges Nogrady in the late 1960s [2]. Rapamycin was observed to inhibit the growth of eukaryotic cells, following which research was carried out regarding its mechanism. This led to the discovery of the protein target of rapamycin (TOR) in yeast that was responsible for the inhibition of growth. Additionally, researchers also discovered a mammalian counterpart, mTOR in 1994.

TOR is a serine/threonine protein kinase that belongs to the (fun to say) phosphatidylinositol kinase-related kinase (PIKK) family [3]. Initially, TOR1 and TOR2 in yeast were thought to regulate the cell cycle but recent studies on the role of TOR in aging indicate that TOR inactivation by deletion or rapamycin leads to an arrest in part of the cycle and a starved phenotype – a state that is better than it sounds. Such discoveries suggest that chronic rapamycin can serve as a potential antiaging compound that mimics diet restriction.

Researchers further indicated cell and organism size was another factor that could determine lifespan. They reported that long-lived Snell pituitary dwarf mice possessed an equal number of skeletal muscle fibers as the wild type. However, the fiber size in pituitary dwarfs was found to be smaller as compared with the wild type. This indicated pituitary dwarfs lacked growth hormone due to reduced mTOR activity observed in the muscle and liver.

Although rapamycin is a dangerous drug for chronic use in humans, it is still used in the treatment of cancer and to suppress the rejection of transplants. This led ITP to test the role of rapamycin in aging, a test that involved the administration of encapsulated rapamycin to 20 months old mice of both sexes. The results reported that rapamycin caused mice to live longer and healthier, with females being the most benefited.

How does rapamycin work?

The mTOR genes, mTORC1 and mTORC2 are structurally and functionally conserved in eukaryotes, including plants. The defining feature of mTOR is the FK506 binding protein (FKBP)-rapamycin binding (FRB) region which is located at the N-terminus of the kinase domain and interacts with the FKBP12-rapamycin complex. The evolution of FRB took place to interact with phosphatidic acid (PA) which serves as the “gatekeeper” for FRB interactions as well as activates and stabilizes the mTOR complexes [1].

Interaction with the FKBP12-rapamycin complex inhibits mTOR which prevents translation of the TOR pathway components, thereby increasing lifespan.

Impact of chronic rapamycin on age-associated diseases

Several studies in mice reported chronic rapamycin slowed aging and improved a few of the age-associated phenotypes. However, two adverse outcomes, nephrotoxicity (rapid deterioration in kidney function) and testicular degeneration (as bad as it sounds) were also reported in those treated mice. A 2014 study indicated that chronic rapamycin suppressed cancer instead of slowing aging, and since then, there has been an increase in research into the role/mechanism of rapamycin or sirolimus in cancer treatment – just check out the numbers on PubMed.

A previous study in the Rb1+/− neuroendocrine tumorigenic model showed diet restriction to have little effect on tumor prevention and lifespan. However, treatment with rapamycin showed lifespan extension as well as a delay in tumor development. Moreover, another study reported that enterically delivered rapamycin could delay the progress of colorectal cancer and extend the lifespan in certain mice [1]. Several other clinical trials are underway to determine the impact of rapamycin on cancer, and a few studies also indicated that along with preventing age-associated diseases, rapamycin could also promote positive longevity effects.

Although most studies indicated rapamycin to be beneficial as an antiaging drug, a few reported adverse outcomes. Rapamycin was reported to increase mortality in a mouse model with type 2 diabetes as a result of suppurative inflammation. Another study reported an adverse event on the administration of intravitreal sirolimus in age-related macular degeneration (AMD).

Next steps

The authors observe that several studies have observed chronic rapamycin to reduce the hallmarks of aging, noting: “This bodes well for an extremely exciting future for research deeper into mTOR system in aging and its diseases [1].”

While rapamycin has been observed to prevent age-associated diseases and promote health, and the authors make the point that further research is required to determine the accurate role of the mTOR system in aging and its diseases. Sharp and Strong note particularly the ongoing studies of rapamycin effects on a non-human primate, the common marmoset, and hope this research will provide “vital information to the practical application to clinical practice.” 

[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

Image: liu yu shan / Shutterstock.com