Rapamycin (and its analogues) is the powerful mTOR inhibitor [and ITP favorite] that has extended the lifespan of organisms from yeast, worms, flies, and even middle-aged mice. The physician with arguably the largest clinical experience in prescribing Rapamycin for longevity talks about the challenges and benefits of this fascinating and controversial practice. Dr Alan Green takes us on a deep dive on the use of Rapamycin for longevity.

Take away points: 

-Rapamycin has extended the lifespan of organisms from yeast, worms, flies, to even middle-aged mice.

-In a 2014 paper, rapamycin extended the median lifespan 23% in male mice and 26% in female mice. 

-It is an FDA approved prescription drug with indications for use for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis.

-The drug requires a prescription and should only be used under supervision of a physician

-Rapamycin acts by suppressing the master nutrient sensing protein mTOR [mechanistic target of Rapamycin]

02:45 Blagosklonny papers (Blagosklonny 2019)

05:23 Jane Mannick rapalogue paper (Mannick 2014)

08:04 Cardiomyopathy diagnosis : Apical hypertrophic cardiomyopathy

09:14 Elevated mTOR as common factor- Inflammation, fibrosis,

12:03 Rapamycin role to decrease mTOR overview common pathway

14:23 mTOR is essentially command and control of the cell for the last 2 billion years

15:00 Mitochondrial complex 1 affected by common pathway by rapamycin, caloric restriction, protein restriction, methionine restriction has universal anti-aging effects

16:05 Increased mTOR causes increased innate immune system/inflammation

17:28 2009 paper showed increased mouse lifespan not by just decreasing cancer but most other diseases of aging

19:15 Osteoarthritis inflammation improved by decreased mTOR and increased autophagy

23:00 Alzheimer disease as a disease of senescent cells

26:00 importance of dose timing for Rapamycin

27:00 Anti aging effects on mTOR1 and other effects on mTOR2

32:00 Rapamycin as off patent drug

37:00 Dosing considerations and subjective effects

40:00 Tracking HOMA-IR  (Homeostatic Model Assessment for Insulin Resistance) score

42:00 Improvement in exercise related to maximum cardiac output

45:00 Age associated cardiomyopathy

49:00 Untoward effects- Aphthous ulcers and decreased innate immune system. Be on guard for bacterial infections.

57:00 Personal lifestyle choices

https://www.mdcalc.com/homa-ir-homeostatic-model-assessment-insulin-resistance

https://rapamycintherapy.com/

Blagosklonny, Mikhail V. “Rapamycin for Longevity: Opinion Article.” Aging 11, no. 19 (October 4, 2019): 8048–67. https://doi.org/10.18632/aging.102355.

Harrison, David E., Randy Strong, Zelton Dave Sharp, James F. Nelson, Clinton M. Astle, Kevin Flurkey, Nancy L. Nadon, et al. “Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice.” Nature 460, no. 7253 (July 2009): 392–95. https://doi.org/10.1038/nature08221.

Mannick, J. B., G. Del Giudice, M. Lattanzi, N. M. Valiante, J. Praestgaard, B. Huang, M. A. Lonetto, et al. “MTOR Inhibition Improves Immune Function in the Elderly.” Science Translational Medicine 6, no. 268 (December 24, 2014): 268ra179-268ra179. https://doi.org/10.1126/scitranslmed.3009892.

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