Rapamycin: A Key to Longevity?
Rapamycin, also known as Sirolimus, is a fascinating compound that has captured the attention of scientists worldwide. Originally discovered in a soil sample from Easter Island (Rapa Nui) in the 1970s, rapamycin was initially used as an antifungal agent.¹ However, it quickly became apparent that this compound had far more significant properties. Today, rapamycin is primarily used as an immunosuppressant to prevent organ transplant rejection.² But recent studies suggest that it may also hold the key to promoting longevity.
Rapamycin and Longevity
The link between rapamycin and longevity was first discovered in a landmark study conducted in 2009. Researchers found that administering rapamycin to middle-aged mice extended their lifespan by up to 14% for females and 9% for males.³ This was a groundbreaking discovery, as it was the first time a pharmaceutical intervention had been shown to increase the lifespan of a mammalian species.
But how does rapamycin promote longevity? The answer lies in a cellular pathway known as the mTOR (mechanistic target of rapamycin) pathway. The mTOR pathway is a central regulator of cell growth and metabolism. When nutrients are abundant, the mTOR pathway promotes cell growth and proliferation. However, when nutrients are scarce, the mTOR pathway is inhibited, triggering a state of cellular maintenance and repair.⁴
Rapamycin works by inhibiting the mTOR pathway, mimicking the state of nutrient scarcity and promoting cellular maintenance and repair. This, in turn, can help to delay the onset of age-related diseases and extend lifespan.⁵
Molecular Mechanisms of Rapamycin
Rapamycin exerts its effects by binding to a protein called FKBP12. The resulting complex then binds to mTOR, inhibiting its activity.⁶ This inhibition of mTOR has several downstream effects. It reduces protein synthesis, inhibits cell growth and proliferation, and promotes autophagy, a process by which cells recycle their own components.⁷
Autophagy is particularly important for longevity. As we age, our cells accumulate damage and waste products. Autophagy helps to clear out this cellular "garbage," maintaining cellular function and health.⁸ By promoting autophagy, rapamycin may help to keep our cells youthful and healthy, potentially extending lifespan.
Other Benefits and Uses of Rapamycin
In addition to its potential longevity-promoting effects, rapamycin has several other benefits and uses. It has been shown to improve immune function in elderly humans, potentially protecting against infectious diseases.⁹ It also has anti-cancer properties and is currently being investigated as a potential cancer treatment.¹⁰ The usage for cancer has a lot to do with how it inhibits cell growth and proliferation, therefore, it will probably be used as an add-on therapy to traditional chemo therapies.
Even though it seems like rapamycin is a wonder drug it's important to note that it’s not without side effects. These can include mouth ulcers, diarrhea, and impaired wound healing.¹¹ Therefore, while the potential benefits of rapamycin are exciting, further research is needed to fully understand how to optimize its usage for longevity purposes.
Takeaway
Rapamycin is a fascinating compound with a wide range of effects. Its ability to promote longevity and health is particularly exciting and could have significant implications for our understanding of aging and disease. As research continues, it will be interesting to see what other secrets this remarkable compound holds.
References
1: Sehgal, S. N. “Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.” Clinical biochemistry 31.5 (1998): 335–340.
2: Stallone, Giovanni, et al. “Sirolimus for Kaposi’s sarcoma in renal-transplant recipients.” New England Journal of Medicine 352.13 (2005): 1317–1323.
3: Harrison, David E., et al. “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.” nature 460.7253 (2009): 392–395.
4: Laplante, Mathieu, and David M. Sabatini. “mTOR signaling in growth control and disease.” Cell 149.2 (2012): 274–293.
5: Johnson, Simon C., Peter S. Rabinovitch, and Matt Kaeberlein. “mTOR is a key modulator of ageing and age-related disease.” Nature 493.7432 (2013): 338–345.
6: Brown, Eric J., et al. "A mammalian protein targeted by G1-arresting rapamycin-receptor complex." Nature 369.6483 (1994): 756-758.
7: Kim, Joungmok, et al. "mTOR: a pharmacologic target for autophagy regulation." The Journal of clinical investigation 125.1 (2015): 25-32.
8: Rubinsztein, David C., Guillermo Mariño, and Guido Kroemer. "Autophagy and aging." Cell 146.5 (2011): 682-695.
9: Mannick, Joan B., et al. "mTOR inhibition improves immune function in the elderly." Science translational medicine 6.268 (2014): 268ra179-268ra179.
10: Benjamin, Don, et al. "Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells." Cell reports 25.11 (2018): 3047-3058.
11: Stallone, Giovanni, et al. "Sirolimus for Kaposi’s sarcoma in renal-transplant recipients." New England Journal of Medicine 352.13 (2005): 1317-1323.
