Rapamycin and its role in aging

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

Until 2009, researchers believed that aging was simply not curable, or if it was, only growth factors would be able to impact the seemingly inexorable process. Two scientific approaches were available that could delay age-related restrictions of diet and/or growth factors by genetic means. People generally aren’t crazy about restricting their diets or having their genes manipulated, so these approaches have been deemed unsuitable for use in humans.

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

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

A new study a Experimental gerontology analyzed the 2009 ITP trial of the drug rapamycin, and authors Zelton Dave Sharp and Randy Strong reflect on 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) first isolated from soil samples obtained from Easter Island by Georges Nogrady in the late 1960s [2]. Rapamycin has been observed to inhibit the growth of eukaryotic cells, as a result of which research has been conducted into its mechanism. This led to the discovery of the rapamycin target protein (TOR) in yeast, which is responsible for growth inhibition. Additionally, researchers also discovered a mammalian counterpart, mTOR in 1994.

TOR is a serine/threonine protein kinase that belongs to the (funny to say) family of phosphatidylinositol-related kinases (PIKK) [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 inactivation of TOR by deletion or rapamycin leads to an arrest in one part of the cycle and a starving phenotype one been better than it looks. Such findings suggest that chronic rapamycin may serve as a potential antiaging compound that mimics dietary restriction.

The researchers also indicated that cell and organism size was another factor that could determine life span. They reported that the long-lived Snell pituitary dwarf mice possessed equal numbers of skeletal muscle fibers compared to the wild type. However, the fiber size in pituitary dwarfs was found to be smaller than in the wild type. This indicated that the pituitary dwarfs lacked growth hormone due to reduced mTOR activity observed in 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 transplant rejection. This led ITP to test the role of rapamycin in aging, a test that involved administering encapsulated rapamycin to 20-month-old male and female mice. The results reported that rapamycin made the mice live longer and healthier, with females benefiting the most.

How does rapamycin work?

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

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

Impact of chronic rapamycin on age-associated diseases

Several mouse studies reported that chronic rapamycin slowed aging and improved some of the age-associated phenotypes. However, two adverse outcomes, nephrotoxicity (rapid deterioration of kidney function) and testicular degeneration (as severe as this sounds) were also reported in 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 the numbers on PubMed.

A previous study in the Rb1+ neuroendocrine tumorigenic model showed that dietary restriction has little effect on tumor prevention and lifespan. However, treatment with rapamycin has been shown to extend lifespan and delay tumor development. In addition, another study reported that enterally administered rapamycin could delay the progression of colorectal cancer and extend lifespan in some mice. [1]. Several other clinical trials are underway to determine the impact of rapamycin on cancer, and some studies have also indicated that, in addition to preventing age-related diseases, rapamycin may also promote positive effects on longevity.

Although most studies have indicated that rapamycin is beneficial as an antiaging drug, some have reported adverse outcomes. Rapamycin has been reported to increase mortality in a mouse model of type 2 diabetes due to suppurative inflammation. Another study reported an adverse event of intravitreal sirolimus administration in age-related macular degeneration (AMD).

Next steps

The authors note that several studies have observed chronic rapamycin reduce the hallmarks of aging, noting, ‘This bodes well for an extremely exciting future for more in-depth research into the mTOR system in aging and its diseases. [1].”

While rapamycin has been observed to prevent age-associated diseases and promote health, the authors emphasize that more research is needed to determine the precise role of the mTOR system in aging and its diseases. Sharp and Strong particularly note ongoing studies on the effects of rapamycin on a nonhuman primate, the common marmoset, and hope this research will provide “information vital for 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

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