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INTRODUCTION

 

Humans are plagued with diseases that are strongly related to ageing : Atherosclerosis, hypertension, diabetic complications, cancer, Alzheimer, Dementia and Parkinson diseases, age-related macular degeneration, osteoarthritis and osteoporosis to name a few. They all have ageing at the core of their pathology in some way or the other.

Hence, suppression of aging itself  should be extensively studied to prevent age-related diseases and, therefore, to extend a healthy and maximal life span.

The entire study of slowing down ageing is a universe in itself hence we would like to focus on just Rapamycin and M-TOR in this article.

 

What is Rapamycin and how did humans find it? ( Historical context ) :

 

In the 1970s, a soil sample from Easter Island was found to contain a bacterial strain, Streptomyces hygroscopicus, that produced a potent antifungal metabolite. This metabolite was purified and found to be a macrocyclic lactone, which was named rapamycin.

 

Rapamycin was found to inhibit proliferation of mammalian cells and to possess immunosuppressive properties. Rapamycin has been used for decades since then  to suppress the immune system in transplant patients. 

Since it has been used as an immunosuppressant for so long no one thought by fair logic that it could work as a drug that slows down ageing

A immunosuppressant for slowing down ageing ? Sounds pretty counterintuitive but therein lies the wonder of this drug! 

 

MECHANISM OF ACTION :

M-TOR is really central to the mechanism of action of rapamycin. 

M-TOR stands for mechanistic target of rapamycin 

 

You can visualize M-TOR to be like CPU of a computer. It is a master pathway which is central to regulation of  umpteen number of processes under various stimuli- external or internal – in our body and rapamycin is one of the drugs which inhibits it. 

 

 

 

First Mechanism of action :

 

Rapamycin helps to prevent age-related disease

by using the TOR pathway and decreasing apoptosis. 

 

TOR is a protein kinase and is  expressed in the cells of nearly all eukaryotic organisms including you and I.  

                                          

It handles a host of cellular functions related to nutrient sensing and growth, including proliferation, transcription, and programmed cell death.                       

                                          

Almost any kind of stress you put on cells is handled by TOR.   

                                          

In humans and other mammals, it is involved with the nervous system, the muscles, all your organs.             

                                          

Inhibiting TOR with rapamycin limits cell proliferation, transcription and most importantly Programmed cell death or Apoptosis. 

                                          

                Rapamycin ,hence ,is used as an age delaying drug!

 

 

Second Mechanism of action:

 

Rapamycin upregulates autophagy in the body

 

Autophagy is a highly conserved lysosomal pathway.  

It plays a role in the recycling of the cytosol and removal of superfluous or damaged organelles. 

 

M-TOR – the master regulator that integrates inputs from the external and internal signals, such as growth factors, amino acids, glucose and energy status to control growth and metabolism and plays an important role in homeostasis also inhibits autophagy under nutrient rich 

                                       

The down-regulation of mTOR activity by rapamycin hence upregulates autophagy  

                                         

Cells via autophagy remove unnecessary or disfunctional components

 +

  recycle cellular components. 

 

Downregulated autophagy is associated with the pathogenesis of many diseases, including cancer, neurodegeneration, heart disease, certain kidney diseases and osteoarthritis. 

Hence , increasing and correcting autophagy works wonders to treat many diseases. 

                                            

                                        

Third Mechanism of Action: 

 

Rapamycin also binds to an intracellular cytoplasmic receptor, the FK506-binding protein 

   

The Rapamycin-FKBP12 complex inhibits cytokine stimulated T lymphocyte proliferation

  

This further leads to exhibiting  multiple effects of Rapamycin, including anti-proliferation, anti-inflammation, anti-fibrosis, and anti-tumour activities. 

 

 

How have we rendered it useful for us ?

 

CURRENT USES:

 

  1. As immunosuppressive agent in Liver and Renal transplant 

 

  • Rapamycin is used in combination with other immunosuppressive agents, namely calcineurin inhibitors and glucocorticoids, to prevent transplant rejection. The basic and initial use of the drug.       
  • It has been found to be an effective immunosuppressant as well as an antiproliferative agent. 
  • It inhibits the response to IL-2 and thereby blocks activation of T cells and B cells. The mode of action of sirolimus is to bind an intracellular protein, FK-binding protein, 
  • Inhibition of target of rapamycin activation results in the inhibition of T-lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation, and the inhibition of antibody production.
  • The chief advantage rapamycin has over calcineurin inhibitors is that it is less toxic to kidneys.

 

2) RAPAMYCIN AND CANCER TREATMENT 

 

M-TOR , as we have have discussed very briefly plays a central role in cell proliferation, transcription,apoptosis. 

A tumour cell wants no regulatory mechanism

which stops its uncontrolled cell division and proliferation hence when we look at a tumor it has MTOR activated in it – indicated in the figure below: 

 

Figure : M-TOR is very active in cancer compared to the control.

 

To simplify it to the utmost switching off MTOR could control cancer and is the basis of numerous trails of rapamycin and MTOR inactivators to curb cancer.

Rapamycin is already being used to cure

Renal cell carcinoma and benign prostatic hyperplasia.

 

 

Table : Trails of rapamycin for Cancer treatment

 

 

POTENTIAL FUTURE USES AND EXPERIMENTATIONS ONGOING FOR USE OF RAPAMYCIN OR ANY DRUG WHICH WORKS BY INHIBITING M-TOR :

  1. Prevention of insulin resistance and diabetic complications by rapamycin

  • Nutrients (glucose and amino and fatty acids), insulin, growth factors, hormones, and oxygen all activate mTOR (target of rapamycin)

  • In turn, mTOR drives both growth and aging and regulates glucose and lipid metabolism.

    Overactivation of mTOR by nutrients and insulin causes characteristic metabolic alterations.

    For example, over-activation of mTOR can cause insulin resistance in humans and has been implicated in type 2 diabetes

  • Rapamycin prevents insulin resistance caused by nutrient infusion in humans, diminishes insulin resistance in diabetic and hyperinsulinemic rats and normalizes glucose metabolism in diabetic mice

 

 Figure : Over-activated by nutrients and insulin, mTOR causes noticeable metabolic effects that are reversible by rapamycin.

 

  • The harmful effects of diabetes are related mostly to its complications, which include nephropathy. In both rats and mice, rapamycin prevents or ameliorates diabetes.                                       

For example, hyper-activation of mTOR in   podocytes leads to diabetic nephropathy and premature death in mice, preventable by rapamycin. 

 

The burden of diabetes is very high in both developing and developed nations. 

India alone has 8 crores of patients of diabetes.

RAPAMYCIN can radicalise treatment of type 2 diabetes complications and insulin resistant diabetes. 

 

  1. Anti-Aging  treatment

 

The Drexel University College of Medicine conducted an experiment and participants over age 40 applied rapamycin cream every 1-2 days to one hand and a placebo to the other hand for eight months.

 

These were the results :

  • majority of the rapamycin hands showed increases in collagen protein, and statistically significant lower levels of p16 protein, a key marker of skin cell aging. 
  • Skin that has lower levels of p16 has     fewer senescent cells, which are associated with skin wrinkles. 

 

  • Beyond cosmetic effects, higher levels of p16 can lead to dermal atrophy, a common condition in seniors, which is associated with fragile skin that tears easily, slow healing after cuts and increased risk of infection or complications after an injury.

 

Figure :

A)Topical rapamycin treatment reduces expression of the senescence regulator p16

B) Topical rapamycin reduces signs of photoaging. Hematoxylin-eosin stain of human skin biopsies from the dorsal hands following application of topical cream containing rapamycin. A reduction in the presence of these histologic markers of age-damaged skin was noted in multiple patient biopsies treated with rapamycin.

C) Topical rapamycin improves cytokeratin  distribution in human skin.

 

Figure: Topical rapamycin increases collagen VII in the basement membrane of human skin.

 

  1. Drug-eluting stent for restenosis and coronary artery lesions

 

The treatment  of coronary artery disease is done by bare-metal stent (BMS ) but in 15-35% cases there is a chance of restenosis.  Rapamycin acts like an anti-proliferation agent in drug eluting stents and has been found to reduce the risk of late stent thrombosis and chronic restenosis. 

             

With its antiproliferative and immunosuppressive effects, rapamycin inhibits the function of mTOR, which is a regulator of cell metabolism and cell proliferation.

This inhibition arrests the cell cycle at G1 phase, reducing the neointimal hyperplasia and therefore decreasing the rate of a restenosis.

 

Since rapamycin is lipid soluble, almost no drug is released into the bloodstream during stent placement and after stent implantation.

Hence Rapamycin coated stents are being tried out to replace bare metal stents by companies like Coracto and Abbot and are in preclinical stages of trial.

 

 

  1. Osteoarthritis and rheumatoid arthritis

 

Osteoarthritis (OA) is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential mechanism that was found to be deficient in aging and OA cartilage.

 

Trials conclusion : 

  • Histopathological exam of synovial tissue showed reduced inflammation where Rapamycin reduced synovial level of IL-1B.
  • Rapamycin lowered mTOR signaling pathway in mouse knee joints and caused activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly reduced in the rapamycin treated group

 

  • Rapamycin treatment also maintained cartilage cellularity and decreased 

ADAMTS-5 and IL-1B expression in articular cartilage 

 

  • ADAMTS-5 is key enzyme which dissolves cartilage resulting in proteolytic matrix destruction. IL-1B is key inflammatory substance and were significantly reduced by rapamycin treatment .

 

 

Conclusion 

 

Rapamycin is a drug that has M-TOR inhibition at the core of mechanism of action. 

One should be surprised how switching of one master pathway by a product of a microbe we stumbled upon by chance can radically treat so many age related diseases and cancer we humans suffer from.  

We have tediously detailed out the mechanism involved in trials of individual disease treatment for readers to appreciate how the mechanism is very basic- “switch off the mTOR” – yet has wonderful consequences. 

  • There are side effects too for sure but we just wanted to focus on the positives in this article. 

 

 

PUBLISHED IN PUBLIC INTEREST BY ;

SNEH SAHANI AND LABIBA S. KHAN

SANTOSH MEDICAL COLLEGE, GHAZIABAD.

 


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