Rapamycin
Rapamycin, also known as sirolimus, is a compound produced by the bacterium Streptomyces hygroscopicus.[1]
It is used in medicine to prevent organ transplant rejection.[2] It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It inhibits activation of T cells and B cells by reducing the production of interleukin-2 (IL-2). Sirolimus is also used as a coating for coronary stents.
Effects on longevity
Rapamycin was first shown to extend lifespan in eukaryotes (actually, yeast cells) in 2006.[3]
In a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment. That is a 9 to 14% increased maximum lifespan. The treatment began in mice aged 20 months, the equivalent of 60 human years.[4][5]
Later, rapamycin has been shown to extend mouse lifespan in several separate experiments.[6][7] It is now being tested for this purpose on nonhuman primates (the marmoset monkey).[8] A study on dogs is also planned.[9][10]
Because rapamycin at high doses can suppress the immune system, people taking rapamycin for transplant or cancer therapy are more susceptible to dangerous infections.[2]
It is thought that some dietary regimes, like restricting calories and methionine, cause lifespan extension by decreasing mTOR activity. It is believed that this is achieved by limiting the essential amino acid leucine, a potent activator of mTOR. The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[11]
According to the free radical theory of aging,[12] reactive oxygen causes damage to mitochondrial proteins, and decreases ATP production. Then, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated.[13] This means the proportion of damaged proteins grows. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[14]
These positive feedbacks on the aging process are counteracted by protective mechanisms: decreased mTOR activity (among other factors) upregulates glycolysis,[14] and removal of dysfunctional cellular components by autophagy.[12]
Rapamycin Media
Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid
A plaque, written in Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau
References
- ↑ Vézina, Claude; Kudelski, Alicia; Sehgal, S. N. (1975). "Rapamycin (AY-22,989), a new antifungal antibiotic". J. Antibiot. 28 (10): 721–6. doi:10.7164/antibiotics.28.721. PMID 1102508.
- ↑ 2.0 2.1 "Rapamune Prescribing Information" (PDF). United States Food and Drug Administration. Wyeth Pharmaceuticals, Inc. May 2015. [1]
- ↑ Powers, R. Wilson; Kaeberlein, Matt; Caldwell, Seth D.; Kennedy, Brian K.; Fields, Stanley (2006). "Extension of chronological life span in yeast by decreased TOR pathway signaling". Genes Dev. 20 (2): 174–84. doi:10.1101/gad.1381406. PMC 1356109. PMID 16418483.
- ↑ Harrison, David E.; Strong, Randy; Sharp, Zelton Dave; Nelson, James F.; Astle, Clinton M.; Flurkey, Kevin; Nadon, Nancy L.; Wilkinson, J. Erby; Frenkel, Krystyna; Carter, Christy S.; Pahor, Marco; Javors, Martin A.; Fernandez, Elizabeth; Miller, Richard A. (2009). "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice". Nature. 460 (7253): 392–5. Bibcode:2009Natur.460..392H. doi:10.1038/nature08221. PMC 2786175. PMID 19587680.
- ↑ "The Times & The Sunday Times". www.thetimes.co.uk. Retrieved 2022-03-26.
- ↑ Miller, Richard A.; Harrison, David E.; Astle, C. M.; Baur, Joseph A.; Boyd, Angela Rodriguez; De Cabo, Rafael; Fernandez, Elizabeth; Flurkey, Kevin; Javors, Martin A.; Nelson, James F.; Orihuela, Carlos J.; Pletcher, Scott; Sharp, Zelton Dave; Sinclair, David; Starnes, Joseph W.; Wilkinson, J. Erby; Nadon, Nancy L.; Strong, Randy (2011). "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice". J. Gerontol. A Biol. Sci. Med. Sci. 66 (2): 191–201. doi:10.1093/gerona/glq178. PMC 3021372. PMID 20974732.
- ↑ Ingram, Donald K.; Roth, George S. (2011). "Glycolytic inhibition as a strategy for developing calorie restriction mimetics". Experimental Gerontology (review). 46 (2–3): 148–154. doi:10.1016/j.exger.2010.12.001. PMID 21167272. S2CID 5634847.
- ↑ Tardif, Suzette; Ross, Corinna; Bergman, Phillip; Fernandez, Elizabeth; Javors, Marty; Salmon, Adam; Spross, Jennifer; Strong, Randy; Richardson, Arlan (2015). "Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset". J Gerontol A Biol Sci Med Sci. 70 (5): 577–588. doi:10.1093/gerona/glu101. PMC 4400395. PMID 25038772.
- ↑ Check Hayden, Erika 2014. (2014). "Pet dogs set to test anti-ageing drug". Nature. 514 (7524): 546. Bibcode:2014Natur.514..546C. doi:10.1038/514546a. PMID 25355339. S2CID 4470407. Retrieved 2 April 2015.
- ↑ Amy, Harmon (16 May 2016). "Dogs test drug aimed at humans' biggest killer: age". The New York Times. https://www.nytimes.com/2016/05/17/us/aging-research-disease-dogs.html. Retrieved 18 May 2016.
- ↑ Cota, Daniela; Proulx, Karine; Smith, Kathi A. Blake; Kozma, Sara C.; Thomas, George; Woods, Stephen C.; Seeley, Randy J. (2006). "Hypothalamic mTOR signaling regulates food intake". Science. 312 (5775): 927–930. Bibcode:2006Sci...312..927C. doi:10.1126/science.1124147. PMID 16690869. S2CID 6526786.
- ↑ 12.0 12.1 Kriete A; Bosl W.J.; Booker G. (2010). "Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses". PLOS Computational Biology. 6 (6): e1000820. Bibcode:2010PLSCB...6E0820K. doi:10.1371/journal.pcbi.1000820. PMC 2887462. PMID 20585546.
- ↑ Magnuson, Brian; Ekim, Bilgen; Fingar, Diane C. (2012). "Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks". The Biochemical Journal. 441 (1): 1–21. doi:10.1042/BJ20110892. ISSN 1470-8728. PMID 22168436.
- ↑ 14.0 14.1 Schieke, Stefan M.; Phillips, Darci; McCoy, J. Philip; Aponte, Angel M.; Shen, Rong-Fong; Balaban, Robert S.; Finkel, Toren (2006). "The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity". J. Biol. Chem. 281 (37): 27643–27652. doi:10.1074/jbc.M603536200. PMID 16847060.