Rapamycin for COVID-19 by Mikhail V. Blagosklonny

Section 11 from forthcoming review entitled “From causes of aging to death from COVID-19” (read full review soon)

As soon as COVID-19 epidemic started, it become clear that COVID-19 vulnerability is aging-dependent condition and the use of rapamycin (Sirolimus) was immediately suggested by independent researches {Sargiacomo, 2020 #9}, {Zhavoronkov, 2020 #105}, {Zhou, 2020 #94}{Omarjee, 2020 #88} {Zheng, 2020 #87}, {Maiese, 2020 #89}, {Lehrer, 2020 #90}. These proposals were based on a mixture of several rationales that need to be clearly distinguished. In theory, there are at least three independent applications of rapamycin and everolimus for COVID-19. Currently, they all are still hypothetical.

  1. Anti-aging effect. By decreasing biological age and preventing age-related diseases, long-term rapamycin therapy may, in theory, decrease COVID-19 mortality rate in the elderly. Anti-aging application is especially important because it is beneficial regardless of COVID-19. After all, the mortality rate from aging and its diseases is 100%, causing 2 million deaths in the USA annually. Prolonged use of rapamycin is expected to improve health, decrease age-related diseases and extend healthy lifespan, rendering individuals less vulnerable, when infected with the virus.
  2. Rejuvenating immunity. As we discussed in section “Figuratively, rapamycin rejuvenates immunity {Blagosklonny, 2015 #79},  mTOR inhibitors can improve immunity to viral infections, improve immunization and vaccination to some viruses such as flu {Araki, 2009 #18}, {Ferrer, 2011 #19}, {Bravo-San Pedro, 2013 #20}, {Feng, 2017 #16}, {Jagannath, 2012 #15}, {Chen, 2009 #43}{Jagannath, 2012 #15} {Bravo-San Pedro, 2013 #20}, {Turner, 2011 #57} {Hurez, 2015 #54} {Mannick, 2014 #75;Mannick, 2018 #76},{Luo, 2014 #42} {Zou, 2012 #45}, {Chen, 2009 #43}, {Ferrer, 2011 #19}.
    In addition, viruses such as flu {Ranadheera, 2018 #96} and coronavirus (MERS-CoV){Kindrachuk, 2015 #95} depend on mTOR activity for replication. Currently, however, there is no data regarding COVID-19. Although aimed to evaluate safety, Phase 1 clinical trial “Sirolimus in COVID-19 Phase 1 (SirCO-1)” may reveal anti-viral effects too https://clinicaltrials.gov/ct2/show/NCT04371640 https://clinicaltrials.gov/ct2/show/NCT04371640
  3. Potential suppression of cytokine storm and hyper-inflammation. As we discussed in the section “Cytokine storm is a hyperfunction”, cytokine storm and hyper-inflammation is a main cause of death in COVID-19 pneumonia {Akhmerov, 2020 #3;Dolhnikoff, 2020 #24;McGonagle, 2020 #4}, {Nikolich-Zugich, 2020 #13;Seminari, 2020 #7;Yao, 2020 #91;Ye, 2020 #10;Zheng, 2020 #87}. {Ye, 2020 #97} {Mehta, 2020 #98}, {Henderson, 2020 #99} {Coperchini, 2020 #100} Rapamycin, an anti-inflammatory agent, inhibits hyper-functions, cellular senescence and decrease secretion of cytokines ({Wang, 2017 #101} {Rolt, 2019 #103}, {Blagosklonny, 2018 #104}. Rapamycin inhibits Jak2/Stat4 signaling pathway {Chiang, 2004 #17} and reduces IF-γ and TNF-α, {Feng, 2017 #16}. Rapamycin (sirolimus) treatment improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure and was associated with improvement in virus clearance, and shortened ventilator days {Wang, 2014 #86}. Clinical trial “Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia (SCOPE)” has been started https://clinicaltrials.gov/ct2/show/NCT04341675