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Is Rapamycin the first step towards a longer life?

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LA
Luis Almeida Nov 22, 2020
Since the dawn of mankind, immortality has been in our sights. While, at least for now, that concept shall remain confined to the realms of science fiction and religion, a solid amount of research has gone into understanding how we can increase our lifespan. Significant efforts have also been made in the field of reversal (rather than prevention or delaying) of biological senescence ; however, no practical solutions exist to reverse aging. Rapamycin is an interesting drug which was isolated from soil samples collected from Rapa Nui (the Polynesian name for Easter Island) in the late 1960s . Following its discovery, other studies demonstrated that it had antibacterial, antifungal, and immunosuppressive activity. It was later found out that this drug inhibits a key player of cellular metabolism, which was coined as the “Mammalian Target Of Rapamycin”: mTOR . While rapamycin never saw much use as an antibiotic or antifungal, rapamycin is one of the core immunosuppressive drugs currently available. It is currently approved by the Food and Drug Administration as prophylaxis for transplant rejection . Some years later, different groups started testing rapamycin (as a way to achieve mTOR inhibition) in the context of aging. Strikingly, rapamycin was shown to ubiquitously prolong longevity in different flies, worms, and mice . In the case of mice, a transient treatment with rapamycin for only three months starting at 20 months of age (equivalent to about 60-65 years old in humans), increased their life expectancy by about 50% longer than untreated mice. Furthermore, muscle strength and motor coordination were also improved in rapamycin-treated mice . However, mice have relatively short lifespans, and these findings may not be directly translatable into humans. The next clues towards understanding if humans may benefit from rapamycin when it comes to living longer might come from dogs. There is an ongoing 5-year clinical trial, aiming to demonstrate if dogs can benefit from rapamycin treatment, and the first results are expected to be known within this decade .
With that said, some open questions remain: 1 – Will Rapamycin be effective in delaying aging in humans? If so, by how much?
2 – What would the right treatment be? mTOR has a central role in organismal metabolism, from immune cell function to muscle growth. What are the consequences of long-term mTOR inhibition?
3 – Immunosuppressive drugs, in general, can facilitate the development of cancer, due to their effect on immune cells. However, Rapamycin is also used as an anti-cancer agent. Will this be an important factor to take into account?
4 – How does rapamycin, and mTOR inhibition, lead to slower aging? mTOR is a central metabolic hub and inhibiting it leads to widespread metabolic changes. If we understand which of those are responsible for rapamycin’s longevity benefits, we may be able to develop a more tailored pharmacological anti-aging drug.
What are your thoughts on rapamycin? I noticed we had a discussion ongoing on the benefit of combining rapamycin with metformin, but there seemed to be a lack of information regarding the benefits of rapamycin per se. A recent opinion article went as far as saying that "not taking rapamycin may be even more dangerous than smoking" .

[1]Rožman, P., How Could We Slow or Reverse the Human Aging Process and Extend the Healthy Life Span with Heterochronous Autologous Hematopoietic Stem Cell Transplantation. Rejuvenation Res, 2020. 23(2): p. 159-170.

[2]Sehgal, S.N., H. Baker, and C. Vézina, Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo), 1975. 28(10): p. 727-32.

[3]Laplante, M. and D.M. Sabatini, mTOR signaling in growth control and disease. Cell, 2012. 149(2): p. 274-93.

[4]Seto, B., Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. Clin Transl Med, 2012. 1(1): p. 29.

[5]Harrison, D.E., et al., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009. 460(7253): p. 392-5.

[6]Kapahi, P., et al., Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol, 2004. 14(10): p. 885-90.

[7]Vellai, T., et al., Genetics: influence of TOR kinase on lifespan in C. elegans. Nature, 2003. 426(6967): p. 620.

[8]Bitto, A., et al., Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. 2016. 5.

[9]Kim, A., Wanted: 10,000 dogs for the largest-ever study on aging in canines, in CNN Health. 2019.

[10]Blagosklonny, M.V., Rapamycin for longevity: opinion article. Aging (Albany NY), 2019. 11(19): p. 8048-8067.

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Creative contributions

2. Intermittent doses of Rapamycin

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
There have been a few trials on the geriatric population that have reported an optimal dosage. However, they mention that Rapamycin treatment is best when tailor-made. Here are some beneficial dose regimes that were reported for anti-aging treatment:
  1. A daily 1 mg/day for several weeks in the elderly did not have side-effects.
  2. Rapalogs such as RAD001 (consistently inhibit only S6 kinase) and BEZ235 (at high concentrations, inhibits TORC1, TORC2, and PI3K and at low concentrations (≤20 nM), inhibits S6K and translation initiation factor 4E-binding protein 1 (4EBP1) phosphorylation) enhance immune function. Therapy: BEZ235 (10 mg daily) and RAD001 (0.1 mg daily).
  3. A weekly high dose (2 mg/kg) instead of low daily doses may avoid side-effects and increase benefits (since a weekly high dose attains a high blood peak level, which is beneficial) in rats.
Theoretically, a pulse (intermittent) dose of Rapamycin might improve the regeneration of stem cells. This is because Rapamycin is required to activate or rejuvenate the stem cells. However, it needs to be withdrawn for the rejuvenated stem cells to induce regeneration and healing (Rapamycin impairs healing). Rapamycin treatment is intended to be lifelong and can be intermittently discontinued if any side-effects occur.

[1]Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol [Internet]. 2018 May;105:53–69. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0531556517309130

[2]Mannick JB, Morris M, Hockey H-UP, Roma G, Beibel M, Kulmatycki K, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med [Internet]. 2018 Jul 11;10(449):eaaq1564. Available from: https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aaq1564

[3]Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. Journals Gerontol Ser A Biol Sci Med Sci [Internet]. 2016 Jul;71(7):876–81. Available from: https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/glw064

[4]Blagosklonny M V. Aging, Stem Cells, and Mammalian Target of Rapamycin: A Prospect of Pharmacologic Rejuvenation of Aging Stem Cells. Rejuvenation Res [Internet]. 2008 Aug;11(4):801–8. Available from: https://www.liebertpub.com/doi/10.1089/rej.2008.0722

3. Rapamycin eliminates hyper-immunity

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
Rapamycin eliminates hyperimmunity, that is, it improves immunity in cancer patients and the elderly, and improves anticancer and antipathogen immunity in mice. Rapamycin is the most effective cancer-preventive agent. Rapamycin and Everolimus are indicated in almost all age-related disease like cancer, obesity, neurodegeneration, and atherosclerosis. Rapamycin prevents cancer more effectively than treats it. No study has shown that Rapamycin causes cancer (published in 2019). More trials with a longer follow-up period are required to ascertain these observations.

[1]Svatek RS, Ji N, de Leon E, Mukherjee NZ, Kabra A, Hurez V, et al. Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer. Cancer Immunol Res [Internet]. 2018 Dec 18; Available from: http://cancerimmunolres.aacrjournals.org/lookup/doi/10.1158/2326-6066.CIR-18-0336

[2]Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med [Internet]. 2014 Dec 24;6(268):268ra179-268ra179. Available from: https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3009892

[3]Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol [Internet]. 2013 Dec 20;14(12):1266–76. Available from: http://www.nature.com/articles/ni.2741

[4]Blagosklonny M V. Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. Cell Cycle [Internet]. 2006 Sep 15;5(18):2087–102. Available from: https://www.tandfonline.com/doi/full/10.4161/cc.5.18.3288

[5]Blagosklonny M V. Rapamycin for longevity: opinion article. Aging (Albany NY) [Internet]. 2019 Oct 4;11(19):8048–67. Available from: http://www.aging-us.com/article/102355/text

4. TOR is beneficial early and damaging later on in life

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
The TOR (nutrient sensing) pathway is activated by nutrients, insulin, and growth factors. TOR increases protein synthesis, inhibits autophagy, and may develop compensatory resistance to insulin, growth hormone, and growth factors. TOR drives geroconverison (from quiescence to senescence), which lasted 3-6 days in cell culture and takes decades in the human body. mTOR makes the cells hypertrophic and leads to SASP, which then causes age-related pathologies. There is no natural bodily inhibitor of TOR. Rapamycin inhibits TOR.

TOR is an example of antagonistic pleiotropy, where it is essential in early life but detrimental in later life. Hence, there is no natural bodily inhibitor of TOR. According to the hyperfunction theory, aging is not programmed, but quasi-programmed (a purposeless continuation of a developmental program that was essential in early life and did not switch off later in life) and driven in part by mTOR. Therefore, TOR-derived (in part) aging causes damage and not the other way around.

[1]Demidenko ZN, Blagosklonny M V. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle [Internet]. 2008 Nov 5;7(21):3355–61. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.7.21.6919

[2]Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells. Mol Cell Biol [Internet]. 2004 Aug 1;24(15):6710–8. Available from: https://mcb.asm.org/content/24/15/6710

[3]Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells. Mol Cell Biol [Internet]. 2004 Aug 1;24(15):6710–8. Available from: https://mcb.asm.org/content/24/15/6710

[4]Blagosklonny M V. Aging: ROS or TOR. Cell Cycle [Internet]. 2008 Nov 5;7(21):3344–54. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.7.21.6965

mTOR is involved in biosynthesis of lipids and related to telomeres

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Brett M.
Brett M. Nov 25, 2020
There may be merit in trying to regulate mTOR activity naturally, such as through intermittent fasting schedules. Just as rapamycin inhibits mTOR, there is also evidence that energy deficits or dietary restrictions can suppress mTOR activity through an increase in AMPK signaling [1,2]. mTOR is known to increase glycolysis [3], so, maybe we don't have to necessarily fast to suppress mTOR, but if we limit carbohydrate intake (i.e., ketogenic dieting), we may be able to "biohack" a suppression of mTOR naturally.

To relate this to longevity, obesity is known to impact the lifespan [4], and the lifespan has been associated with telomere length within the cell [5]. So, perhaps one way that rapamycin may promote healthy aging processes is through suppression of mTOR and thus, lipid biosynthesis and glycolysis, which are both known to increase metabolic demand in the body [6,7], and are both dysfunctional in metabolic disorders such as diabetes. In fact, diabetes mellitus has been associated with telomere shortening [8], and suppressing mTOR was associated with an increase in telomere length in planarians, a type of flatworm [9]. This also may be why ketogenic diets are beneficial to those who suffer from diabetes and other obesity-related complications [10].

These findings, taken together, may hint at a process by which mTOR influences telomere length and, quite possibly, the aging process by interacting and influencing metabolic processes in a manner that can expedite cellular aging.

So, in summary, through intermittent fasting or by supplementing rapamcyin, we may be able to reduce metabolic demand in the body, preserve telomere length, and promote cellular mechanisms associated with longevity (i.e., reducing the proliferate nature of cancer cells, suppress sugar-dependent immune cells in autoimmune disease, etc). Some ideas to think about as to why rapamycin may be related to longevity, I suppose...


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General comments

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Povilas S
Povilas S6 months ago
Thanks for an interesting and informative summary about the drug. I got immediately hooked up due to the fact that it was first discovered on Eastern Island, which is mysterious on its own and is often speculated to have connections with aliens. So the life-prolonging drug produced by local bacteria fits the picture and makes it even more interesting. I wonder if that species of bacteria is only found there or in other places too. There's a lot of info about the drug but very little about the bacteria itself.
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Darko Savic
Darko Savic6 months ago
Povilas Sway to introduce pseudoscience to the platform:)
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Povilas S
Povilas S6 months ago
Darko Savic Yes, I thought about that. But there are two sides to this - pseudoscience and similar topics are naturally interesting to people and might get you fired up about researching the topic more seriously, that's exactly what happened - I then researched about the drug, the bacteria, all the scientific stuff that I wasn't motivated to do before, even though I saw the drug mentioned a few times in other sessions. And that's all because he mentioned Easter Island and the etymology of the drug name, a few interesting facts.
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Darko Savic
Darko Savic6 months ago
Once we do figure out how Rapamycin leads to slower aging maybe derivatives (rapalogs) will be the way to minimize side effects while retaining the benefits