Inhibition of the mTOR pathway extends life span

A new study published in Science Translational Medicine confirms that blocking the mTOR pathway boosts elderly immune systems by up to 20 percent. (1) Before this study, animal experimentation showed that this approach extends life span in mice up to 14 percent, even when treatment is initiated late in life. (2)

Because it would take decades to test the effect of mTOR molecules on life span in humans, the researchers at Novartis Institutes for BioMedical Research  et al used a proxy  called Roo1. (2) The goal was to measure the decline in immune function in seniors’ (age 65 and older) during aging, as assessed by their response to a flu vaccine. (3). They found that R001 boosted immune systems response to a flu vaccine by 20 percent. (4).The researchers also found that R001  reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. (1)

 However, given potential negative side effects, the immune-enhancing effects of mTOR inhibitors need to be verified with additional studies because :

 “…the toxicity of RAD001 at doses used in oncology or organ transplantation results in adverse effects such as stomatitis, diarrhea, nausea, cytopenias, hyperlipidemia, and hyperglycemia.”

Up to now, the inhibition of the mTOR (Mammalian target of rapamycin) pathway has shown to extend life span in all animal species studied to date.

We now have evidence that this Roo1 molecule can also extend the  immune system’s lifespan and slow down immunosenescence in the elderly. Given potential side effects though,  further human research is warranted.

mTOR can be on occasion good, but for most non athletic adults, it needs to be downregulated

For growing adolescents and athelets, mTOR activation helps to put on more muscle  (R) and certain hormones like IFG-1 (R).

This makes evolutionary sense.  When we had food it was a good idea to increase muscle and fat and when we didn’t it made sense to turn our systems down in order to conserve energy. mTOR also increases ATP production and creates new mitochondria, (R) as well as mitochondrial metabolism (by activating PGC1a). (R) mTOR is involved in various forms of synaptic plasticity and memory consolidation.

On the other hand, for most other scenarios, its best to reduce mTOR.  mTOR inhibition for example is helpful in people with PTSD because it blocks reconsolidation of an established fear memory in a lasting manner (R). Too much mTOR activation contributes to a large number of human diseases, including cancer, obesity, type 2 diabetes, depression and neurodegeneration (R).  It can be responsible for acne as well (R).

Futhermore, mTOR is associated with cancer and indeed it increases angiogenesis (via HIF-1a), a process through which new blood vessels form from pre-existing vessels. (R)  This helps cancer grow.

Increased mTOR promotes Th1 and Th17 immunity, leading to increased intestinal inflammation (R), among other issues. It increases Th17 cells by increasing another protein called hypoxia-induced factor (HIF)-1α. (R)

A reduction in mTOR Improves insulin sensitivity in muscle cells. (R)  mTOR increases glycolysis, which is what allows Th17 cells to proliferate. This works through HIF1α. Blocking glycolysis inhibited Th17 development while promoting Treg cell generation. (R)

When T cells (CD4 and CD8) are stimulated – by lectins or other means- they rapidly reproduce.   (R) The rapid production of T Cells requires energy.   Activation of mTOR allows the T Cells to rapidly expand by shifting how they get energy.  Instead of getting energy from the mitochondria (via oxidative phosphorylation), they get it primarily from breaking glucose down (glycolysis). (R)

When the process of glucose breakdown is hindered, T cells realize that they don’t have what it takes to rapidly expand and fight pathogens.  So instead they turn into Treg Cells, which dials the immune system down. (R)

Conclusion

For health and longevity, we’d want systemic mTOR levels to below most of the time, with bouts of activation. It’s preferable to have mTOR more active in your brain and muscles rather than in your fat cells and liver.  Exercise is ideal because it does exactly this. (R)

Pr Joubert

Gerontology. 2018;64(2):127-134. doi: 10.1159/000484629. Epub 2017 Dec 1.

mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review.

Abstract

The mechanistic target of rapamycin (mTOR) network is an evolutionary conserved signaling hub that senses and integrates environmental and intracellular nutrient and growth factor signals to coordinate basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation depending on the individual cell and tissue. A growing list of evidence suggests that mTOR signaling influences longevity and aging. Inhibition of the mTOR complex 1 (mTORC1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied. This review discusses the potential mechanisms how mTOR signaling controls lifespan and influences aging-related processes such as cellular senescence, metabolism, and stem cell function. Understanding these processes might provide novel therapeutic approaches to influence longevity and aging-related diseases.

KEYWORDS:

Calorie restriction; Metabolic reprogramming; Rapamycin

PMID:
29190625
PMCID:
PMC6089343
[Available on 2019-01-01]
DOI:
10.1159/000484629
[Indexed for MEDLINE]

Free PMC Article

Text under construction

REFERENCES

(1). Joan B. Mannick et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med 24 December 2014: Vol. 6, Issue 268.
(2).  In the mice studies,  there were other improvements from a variety of aging-related conditions in old mice, including, but not limited to tendon stiffening, cardiac dysfunction, cognitive decline, and decreased mobility. These comorbidities regressed independently of a specific disease process.
(3). This drug’s full name is  everolimus (or RAD001), a version the well known anti-aging drug called rapamycin (sirolimus). Rapamycin and RAD001 belong to a class of drugs known as “mTOR inhibitors.”  mTOR  means “Mammalian target of rapamycin”.
(4). Immune-system aging is a major cause of disease and death, making older people more susceptible to infections and cancer. They also tend to have a weaker response to vaccines.
The Study’s complete Citation:
J. B. Mannick, G. Del Giudice, M. Lattanzi, N. M. Valiante, J. Praestgaard, B. Huang, M. A. Lonetto, H. T. Maecker, J. Kovarik, S. Carson, D. J. Glass, L. B. Klickstein, mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).
The authors: Joan B. Mannick (1), Giuseppe Del Giudice (2), Maria Lattanzi (2), Nicholas M. Valiante (3), Jens Praestgaard (4), Baisong Huang1, Michael A. Lonetto1, Holden T. Maecker (5), John Kovarik (6), Simon Carson (7), David J. Glass1 and Lloyd B. Klickstein
1 Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
2 Novartis Vaccines and Diagnostics, 53100 Siena, Italy.
3 Novartis Vaccines and Diagnostics, Cambridge, MA 02139, USA.
4 Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
5 Stanford University School of Medicine, Stanford, CA 94305–5124, USA.
6 Novartis Pharmaceuticals Corporation, CH-4002 Basel, Switzerland.
7 Southern Clinical Trials, Christchurch 8024, New Zealand.
Corresponding author. E-mail: joan.mannick@novartis.com

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2015 Copyright. All rights reserved.  Optimal Longevity Institute
Disclaimer. This site is educational and nothing therein should be construed as medical advice.

Professor Joubert teaches how to extend a healthy cancer-free Lifespan to 122 years thanks to safe, efficient and cost friendly breakthrough protocols. Working on a documentary and book that redefines Medicine in light of new discoveries, ancient wisdoms, innovative research and holistic science, he can be nonetheless available to coach patients back to homeostasis, wellbeing & Joie de Vivre. On occasion, Pr. Joubert can also coach health professionals to better protect their holistic practice when they must deviate from outdated and-or irrational mainstream “standards of care” in order to genuinely serve their patients, evidence-strong Science and internationally recognized human rights. For details, see the links called “Contact” and “Mission” (under the “About” link).

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