Rapamycin

2021-05-19T00:22:23Z

Chantelak:

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapmycin is a drug that suppresses the immune system and is used to prevent the rejection of organ transplants by the immune system. Rapamycin is particularly useful in preventing rejection of kidney transplants.<ref>https://en.wikipedia.org/wiki/Sirolimus</ref> The compound was originally named rapamycin after the native name of the island on which it was discovered, Rapa Nui.<ref>https://en.wikipedia.org/wiki/Sirolimus</ref>

Rapamycin has been shown to extend the healthy lifespan in worms, yeast, flies, and mice.<ref>https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA</ref> Several scientists have suggested that rapamycin could be used to slow down aging and all age-related diseases in humans<ref>ncbi.nlm.nih.gov/pubmed/17012837/</ref>, becoming one of the first identified “anti-aging drugs”.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/</ref>

== Evidence of lifespan extension ==
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing lifespan. Rapamycin significantly extends healthy lifespan in approximately 90% of the mice models it has been tested in.<ref>https://link.springer.com/article/10.1007/s11357-020-00274-1</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice.<ref>https://doi.org/10.1038%2Fnature08221</ref> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological agent.

==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in the mice.<ref>https://doi.org/10.1126%2Fscitranslmed.3003802</ref> In one short-lived mutant strain of mice that models that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>https://www.ncbi.nlm.nih.gov/pubmed/24231806/</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with a high dose of rapamycin for only 3 months resulted in a dramatic increase in lifespan of up to 60%.<ref>https://elifesciences.org/articles/16351</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269</ref>

'''Dose response'''

Genetically heterogeneous UMHET3 mice were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose exhibited the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. ''Journal of genetics and genomics= Yi chuan xue bao'', ''41''(9), 459.]]</ref> The optimal dose for longevity in mice remains to be seen, and determining this dose will also require consideration of the side effect profile of rapamycin.<ref name=":0" />

==== Age-related diseases ====
Rapamycin has also been demonstrated to have a major impact on reducing cancer risk, cardiac diseases, and neurodegenerative-like processes in mice.<ref>https://link.springer.com/article/10.1007/s11357-020-00274-1

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=== Dogs ===
There is evidence that rapamycin prevents age-related decline in dogs. Results indicated statistically significant improvements in heart function in the dogs that received rapamycin relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/</ref>

== Mechanism ==

=== Manipulating key metabolic pathways ===
Rapamycin has been described as a 'calorie restriction mimetic' as it acts on the mammalian target of rapamycin (mTOR) metabolic pathway. Fasting and calorie restriction inhibit muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>https://www.ncbi.nlm.nih.gov/pubmed/21179166/</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/#r108

</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/#r181

</ref><ref>[[Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. nature, 460(7253), 392-395.|Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]]</ref> Rapamycin also targets multiple aspects of aging, but in a segmented, tissue-specific manner.

=== Reducing cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is a senomorphic that can inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>https://link.springer.com/article/10.1007/s11357-020-00274-1

</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>https://doi.org/10.1007%2Fs11357-019-00113-y

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== Human Clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is that an optimal dose of rapamycin may extend healthy lifespan.]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The trial aims to systematically investigate the use of rapamycin to promote longevity, and is expected to conclude in 2023.<ref>https://clinicaltrials.gov/ct2/show/NCT04488601</ref> The study will involve over 1,000 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRX, a new company dedicated to developing scientifically proven interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/</ref>

== Regulatory Approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1994 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>https://link.springer.com/article/10.1007/s11357-020-00274-1</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215

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== Safety ==
Rapamycin has been used by millions of people and is generally considered safe in humans, although some side effects have been reported. Use of high-dose rapamycin has been associated with pain, headache, fever, high blood pressure, nausea, abdominal pain, constipation, diarrhea, and other side effects. However, side effects are mostly reversible and represent a worst-case scenario, as these patients are severely ill and taking high doses of the drug along with other medications.<ref>https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(20)30068-4/fulltext

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== Rapalogs ==
Rapalogs are molecules that have a similar mechanism to rapamycin (inhibiting the mTORC1 protein). These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. However, only one rapalog, Everolimus, has been studied in this context.<ref>https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf=</ref>

== References ==

Longevity Wiki - User contributions [en-GB]

Rapamycin