When it comes to regulating aging, an important molecule which has widespread effects is mTOR. mTOR is the acronym for the Mechanistic (previously also called ‘mammalian’) Target of Rapamycin... Rapamycin (also known as sirolimus) is a protein kinase anti-fungal agent that was first discovered in the soils of Easter Island in the 1970s, which has been found to regulate the proliferation and development of cells, and to act as an immunosuppressant. It has been used to dampen the immune response following transplants. Rapamycin also has a positive effect on the heart and brain, particularly in age-related neurodegenerative diseases. mTOR acts as a central controller in signalling pathways which regulate the survival and function of the cell. It can affect cell division processes, the response to stress, and general cell and protein tasks. Figure 1: The impact of mTOR on various aspects of aging.
These signalling pathways are very complicated and depend on many feedback loops, energy supply, and a great variety of other molecules or signals. During certain diseases and aging, the function of mTOR can become deregulated and result in clinical manifestations, [see figure 1]. Despite talking about mTOR as if it is just one molecule, it functions, in fact, as two separate complexes called mTORC1 and mTORC2. (1) Several compounds have now been developed (or discovered) which inhibit some of the actions of mTOR and so improve certain health parameters. Rapamycin and its analogues inhibit the immune response by blocking the proliferation of T-cells and by reducing the impact of interleukin inflammato-
mTOR PATHWAY
TOR = target gene of rapamycin, antibiotic soil organism GROWTH FACTORS NUTRIENTS
CELLULAR STRESS
mTOR inhibitors Rapamycin*, resveratrol *Sirolimus FDAapproved drug
Cell Growth & Multiplication
New Blood Vessel Formation (Angiogenesis)
CELL SURVIVAL Transcription Initiation Factor
PROTEIN MAKING Digestion of Cellular Debris
Cell Metabolism
Stem cell Differentiation
Carcinogenic agents Dedifferentiation
Autophagy IKK-β/NF-KB
Differentiated cell
Dormant cell
DDR
Damaged cell
mTORC1 mTORC2 IIS
Senescent cell
Cell death Calorie restriction
Longevity
ry compounds. They also block the formation of new blood vessels (angiogenesis) which results in cancer cells being deprived of their blood supply. Other mTOR inhibitors have been developed, but most of these are based on the basic rapamycin molecular structure. For example, the rapamycin derivative temsirolimus is a soluble agent which has a reduced risk of side effects compared to rapamycin. Since it is water soluble, it can be administered by intravenous infusion. It is approved by the FDA for the treatment of kidney tumours. Other derivative molecules (called rapalogs, i.e. ‘rapamycin analogues’) are: • Everolimus (approved initially for the treatment of kidney tumours, and more recently for the treatment of breast and pancreatic tumours). • Ridaforolimus (also known as Deforolimus) is used for breast and other cancers.
Metformin Rapamycin Resveratrol Melatonin
Transformed cell
Cancer cell
Figure 2: Metformin, rapamycin and some other compounds with mTOR and insulin/IGF-1-like signalling (IIS)-inhibitory potential (resveratrol, melatonin, etc.) are able to modify both aging and carcinogenesis. Anisimov VN. Metformin and rapamycin are master-keys for understanding the relationship between cell senescent, aging and cancer. AGING, Vol 5, No 5 , pp 337-338.
These drugs bind to the same sites as rapamycin, and are considered to be generally better inhibitors. They can be used orally, as well as by intravenous injection. They work by stopping the growth of some cancers, but are not very effective in all cancers, particularly if used alone. One important mechanism of action of these rapalogs is through competition for the ATP molecule, thus blocking energy supply to tumour cells. Many rapalogs also interfere with apoptosis (loss of damaged cells). This results in increased apoptosis of cancer cells, thereby reducing the size of the tumour. These drugs inhibit both mTORC1 and mTORC2 elements, [see fig 2].
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